Dihydroisoquinoline compound

ABSTRACT

A compound of general formula I: 
                         
is disclosed. The compound be used to prevent or treat hepatitis B virus infection.

This application is the National Stage Application of PCT/CN2018/072057,filed on Jan. 10, 2018, which claims priority to Chinese PatentApplication No.: 201710027443.3, filed on Jan. 13, 2017, which isincorporated by reference for all purposes as if fully set forth herein.

The invention belongs to the field of compounds, in particular to adihydroisoquinoline compound, in particular to a dihydroisoquinolinecompound and a mixture or composition containing dihydroisoquinolinecompound, especially as a dihydroisoquinoline compound and mixtures orcompositions of dihydroisoquinoline compounds used for preventing andtreating hepatitis B virus infection.

FIELD OF THE INVENTION

According to WHO report, one third of the world's current population hadevidences of HBV infection in the past and among them 350 to 500 millionpeople are chronic carriers of HBV. HBV infection causes either acutehepatitis, or chronic hepatitis which will end up with cirrhosis andhepatocellular carcinoma (HCC) at a high probability. HBV can infecthuman via many different routes, leading to transmission of liverdisease. It is estimated that 0.8 million people died because of acuteor chronic HBV infection annually. As a result, HBV infection has becomeone of the major public health problems. Despite that the development ofsafe and effective HBV vaccines and extensive vaccination of new borninfants have significantly reduced the incidence of HBV infection andeven incidence of HCC, the global HBV health burden remains high asvaccination coverage is still low in certain low-income regions and manyHBV patients are denied access of diagnosis and treatment in time due toeconomic reasons. Even though with more fundamental research into HBVinfection inhibition and applications of new diagnostic and treatmentmethods, progress has been made in treatment and prevention of HBVrecently, curing HBV is still not feasible, and it remains a huge unmetmedical need.

The hepatitis B virus (HBV) is an enveloped virus with a partiallysingle-stranded circular DNA genome of 3.2 kb, belonging tohepadnavirdae. HBV displays 8% nucleotide variation over whole genomeand eight genotypes were defined based on the 4.2% nucleotidedifferences in S gene. These genotypes show different geographicdistribution and ethnic distribution. Genotype B and C are mainly foundin Asia; genotype A and D are dominant in Africa, Europe and India;genotype E is most common in West Africa; genotype F is observed inCentral and South America while genotype G is mostly reported in France,German and North America. HBV genome consists of four overlapping openreading frames (ORF), encoding for core, polymerase (Pol), envelope andX-proteins respectively. HBV infectious particle relies on Sodium/bileacid cotransporter (NTCP) on hepatocyte surface for infection, and afterinfection, the partially double-stranded viral DNA is transported intonucleus and converted into covalently closed circular DNA (cccDNA), andthis cccDNA serves as transcription template for viral pre-genomic RNA(pgRNA) and sub-genomic RNAs. The synthesized core protein then packagepgRNA and polymerase together for replication (Lamontagne R J, et al.Hepatoma Res 2016; 2: 163-86.).

On the viral particle surface, there is a 7 nm layer of phospholipidmembrane protein, called hepatitis B surface antigen (HBsAg). The HBsAgconsists of proteins of large, middle and small size. They are encodedby the same S gene translated from three different start codons. Allthree proteins share the same S-domain at their C-termini. Aftersynthesis, these proteins are inserted into ER membrane under theguidance of N-terminal signal peptide. In one aspect HBsAg is assembledinto mature HBV particle as major structure protein, yet at the sametime, it is able to form spherical or filamentous subviral particles(SVPs). The SVPs usually outnumber mature viral particles by at least1000 fold. In serological test, being HBsAg positive for more than sixmonths is marker of chronic HBV infection. Though SVP is not infectious,it can seriously affect host immune response. HBsAg can dampen theactivation of monocytes in the innate immune system (Vanlandschoot P etal, J Gen Virol. 2002 June; 83(Pt 6): 1281-9), jeopardize the functionof dendritic cells (Marjoleine L et al, Immunology. 2009 February;126(2): 280-289.), and disrupt the activity of natural killer cells(Yang Y et al, Int Immunopharmacol. 2016 September; 38: 291-7).Prolonged exposure to HBsAg and other viral antigens results dysfunctionof HBV-specific T cells and leads to immune tolerance of HBV (Carolina Bet al, J Virol. 2007 April; 81(8): 4215-4225). Therefore, serum HBsAglevel is regarded as one of the key biomarkers for prognosis andtreatment response in chronic HBV patient. Serological clearance ofHBsAg is considered as functional cure of CHB.

Until today, FDA has approved two kinds of therapies for HBV interferon(interferon α or pegylated interferon α) and nucleotide/nucleosideanalogs. The nucleoside analogs include lamivudine (heptodin), adefovir(hepsera), entecavir (baraclude), telbivudine (Sebivo), and tenofovir(Viread). By regulating host innate immune system, interferon α is ableto activate immune cells and induce production of multiple anti-viralcytokines to control HBV replication. Besides the anti-viral activity,interferon therapy can enhance host immunity with a long-lasting effect,and reduce risks of cirrhosis and HCC. However, this therapy isassociated with some disadvantages such as unsatisfactory anti-viralpotency, and a plethora of adverse side-effects including flu-likesymptoms, muscle pain, thrombocytopenia, hair loss and depression.Long-term interferon therapy had only achieved 2.25% HBsAg clearancerate in western populations and a merely 0.43% clearance rate in Asianpopulations (C M Chun et al, Antivir Ther. 2010; 15(2): 133-43).Compared to interferon, nucleoside analogs control viral replication bydirectly inhibiting HBV viral DNA synthesis. Lamivudine, a once HIVdrug, shows fast absorption after oral administration and cansignificantly reduce viral load by inhibiting HBV replication. Itdemonstrates both strong antiviral potency and good safety profile withless AE, but resistance mutations emerge after prolonged administrationof this drug. Adefovir is more potent than lamivudine, and it showspotent anti-viral effect even for lamivudine-resistant patients, butlong-term usage of this drug is associated with kidney toxicity. Ingeneral, nucleoside analogs, even with prolonged therapy, havedemonstrated a disappointing HBsAg clearance rate of 0.5-1% in CHBpatients annually (E Loggi et al, Dig Liver Dis. 2015 October; 47(10):836-41).

To summarize it, current anti-HBV therapies are unable to eradicate HBVfrom chronic HBV patient, due to factors such as persistent presence andreplication of HBV in hepatocytes and continues emergence of drugresistant mutations during treatment. To keep viral replication at lowlevel, patients have to undergo long-term treatment and this prolongedtreatment imposes enormous social and economic burden on the society andmedical system. Therefore, curing HBV with a finite treatment representsa huge unmet medical need. Clearance of HBsAg possess the potential tobreak host immune tolerance of HBV, restore host immune response toachieve a cure of HBV, and thus points a new direction for HBVtreatment. Therefore, developing HBsAg inhibitor will offer greatopportunity for HBV treatment and produce enormous social and economicbenefit in the future.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds of general formula I:

wherein:

R is any one of hydrogen and C₁₋₆ alkyl;

R¹ is any one of hydrogen, deuterium, halogen, C₁₋₆ alkyl, C₁₋₆alkylamino, and C₁₋₆ alkoxy;

R² is any one of hydrogen, deuterium, halogen, C₁₋₆ alkyl, C₁₋₆ alkylsubstituted with at least one fluorine, C₃₋₇ cycloalkyl, C₁₋₆alkylamino, C₁₋₆ alkoxy, and heterocycloalkyl;

Ar is any one of phenyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyridin-2(1H)-keto, pyridin-4(1H)-keto, pyrrolyl,pyrazolyl, thiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, imidazolyl,tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl,oxadiazolyl, naphthyl, benzothiophenyl, indolyl, benzimidazolyl,benzothiazolyl, benzofuryl, quinolyl, isoquinolyl, and quinazolinyl;

R³ is any one of hydrogen, deuterium, halogen, cyano, C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy, and heterocycloalkyl;

R⁴ is any one of hydrogen, deuterium, and C₁₋₆ alkyl;

R⁵ is any one of hydrogen, deuterium, C₁₋₆ alkyl, C₁₋₆ alkyl substitutedwith at least one fluorine, and C₃₋₇ cycloalkyl.

Preferably, Ar is substituted with any one or more of deuterium,halogen, hydroxy, amino, cyano, C₁₋₆ alkyl, a substituted C₁₋₆ alkyl,C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxyC₁₋₆ alkoxy, C₁₋₆alkylamino, di-C₁₋₆ alkylamino, C₃₋₇ cycloalkylamino, C₃₋₇heterocycloalkylamino, C₃₋₇ cycloalkyl C₁₋₆ alkylamino, carboxyl C₁₋₆alkylamino, —C₃₋₇ heterocycloalkyl-R⁶, —C(═O)—R⁶, —C₁₋₆ alkyl-C(═O)—R⁶,—S(═O)₂—R⁶, —C₁₋₆ alkyl-S(═O)₂—R⁶, —N(R⁷)—C(═O)—R⁸, —C₁₋₆alkylamino-C(═O)—C₁₋₆ alkyl, and —C₁₋₆ alkylamino-C(═O)-amino C₁₋₆alkyl, wherein the substituted C₁₋₆ alkyl is substituted with any one ormore of fluorine, hydroxy, cyano, aryl, heteroaryl, amino, C₁₋₆ alkoxy,C₁₋₆ alkylamino, C₃₋₇ cycloalkyl, carboxyl, and C₃₋₇ heterocycloalkyl;wherein,

R⁶ is any one of hydroxy, amino, carboxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl,C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇cycloalkylamino, C₃₋₇ heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl;

R⁷ is any one of hydrogen, deuterium, C₁₋₆ alkyl, and C₃₋₇ cycloalkyl;

R⁸ is any one of hydrogen, deuterium, C₁₋₆ alkyl, aryl, heteroaryl, C₃₋₇cycloalkyl, aryl C₁₋₆ alkyl, heteroaryl C₁₋₆ alkyl, and C₃₋₇heterocycloalkyl.

Preferably, R is any one of hydrogen, methyl, ethyl, propyl, isopropyl,and tert-butyl;

R¹ is any one of hydrogen, deuterium, fluorine, chlorine, bromine,methyl, ethyl, isopropyl, tert-butyl, methylamino, ethylamino, methoxy,ethoxy, and isopropoxy;

R² is any one of hydrogen, deuterium, fluorine, chlorine, bromine,methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl,trifluoromethylmethyl, cyclopropyl, cyclopentyl, methylamino,ethylamino, methoxy, ethoxy, isopropoxy, pyrrolidinyl, and morpholinyl;

Ar is phenyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, cyano, methyl, ethyl, trifluoromethyl,trifluoromethylmethyl, hydroxymethyl, cyanomethyl, benzyl,pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,morpholinylethyl, methoxy, and methylamino; or pyrazolyl substitutedwith any one or more of deuterium, fluorine, chlorine, bromine, hydroxy,cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, benzyl,pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, carboxypropyl, morpholinylethyl, methoxy, methylamino,oxetanyl, piperidyl, and ethoxycarbonylethyl; or pyridinyl substitutedwith any one or more of deuterium, fluorine, chlorine, bromine, hydroxy,amino, cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl,methoxymethyl, methoxyethyl, methoxypropyl, methylaminoethyl,morpholinylethyl, morpholinyl, piperidyl, piperazinyl, pyrrolidinyl,azetidinyl, methoxy, methoxyethoxy, methylamino, dimethylamino,cyclopropylamino, cyclobutylamino, cyclopropylmethylamino,4-hydroxypiperidyl, 4-methylpiperazinyl, 4-ethylpiperazinyl,4-acetylpiperazinyl, ethoxycarbonylethyl, acetylamino, andcarboxymethylamino; or 1, 2, 4-triazolyl substituted with any one ormore of deuterium, fluorine, chlorine, bromine, hydroxy, amino, methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,difluoromethyl, trifluoromethyl, trifluoromethylmethyl, hydroxymethyl,hydroxyethyl, hydroxypropyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, and morpholinylethyl; or thiazolyl substituted with anyone or more of deuterium, fluorine, chlorine, bromine, hydroxy, amino,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, aminomethyl,methoxymethyl, methoxyethyl, methoxypropyl, methylaminoethyl,cyclopropylmethyl, carboxymethyl, carboxyethyl, carboxypropyl,morpholinylethyl, oxetanyl, piperidyl, morpholinyl, piperazinyl,4-hydroxypiperidyl, 4-methylpiperazinyl, and ethoxycarbonylethyl; orpyrimidyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, amino, cyano, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxyethyl, cyanomethyl,aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, azetidinyl,piperidyl, piperazinyl, methoxy, methylamino, dimethylamino,cyclopropylamino, cyclopropylmethylamino, 4-ethylpiperazinyl,ethoxycarbonylethyl, 4-carboxypiperidyl, cyclobutylamino,3-carboxypyrrolidinyl, and carboxymethylamino; or pyridin-2(1H)-ketosubstituted with any one or more of deuterium, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxyethyl, cyanomethyl,aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, piperidyl,piperazinyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, andethoxycarbonylpropyl;

R³ is any one of hydrogen, deuterium, fluorine, chlorine, bromine,methyl, ethyl, and cyano;

R⁴ is any one of hydrogen, deuterium, methyl, and ethyl;

R⁵ is any one of hydrogen, deuterium, methyl, ethyl, isopropyl, butyl,sec-butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl,and cyclopropyl.

Preferably, R is any one of hydrogen and C₁₋₆ alkyl;

R¹ is any one of hydrogen, deuterium, halogen, and C₁₋₆ alkyl;

R² is any one of hydrogen, deuterium, halogen, C₁₋₆ alkyl, C₁₋₆ alkylsubstituted with at least one fluorine, C₃₋₇ cycloalkyl, and C₁₋₆alkoxy;

Ar is any one of phenyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyridin-2(1H)-keto, pyridin-4(1H)-keto, pyrrolyl,pyrazolyl, thiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, imidazolyl,tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, andoxadiazolyl;

R³ is any one of hydrogen, deuterium, halogen, cyano, C₁₋₆ alkyl, andC₃₋₇ cycloalkyl;

R⁴ is any one of hydrogen, deuterium, and C₁₋₆ alkyl;

R⁵ is any one of hydrogen, deuterium, C₁₋₆ alkyl, C₁₋₆ alkyl substitutedwith at least one fluorine, and C₃₋₇ cycloalkyl.

Preferably, Ar is substituted with any one or more of deuterium,halogen, hydroxy, cyano, amino, C₁₋₆ alkyl, a substituted C₁₋₆ alkyl,C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy C₁₋₆ alkoxy, C₁₋₆alkylamino, di-C₁₋₆ alkylamino, C₃₋₇ cycloalkylamino, C₃₋₇heterocycloalkylamino, C₃₋₇ cycloalkyl C₁₋₆ alkylamino, carboxyl C₁₋₆alkylamino, —C₃₋₇ heterocycloalkyl-R⁶, —C(═O)—R⁶, —C₁₋₆ alkyl-C(═O)—R⁶,—S(═O)₂—R⁶, —C₁₋₆ alkyl-S(═O)₂—R⁶, and —N(R⁷)—C(═O)—R⁸, wherein thesubstituted C₁₋₆ alkyl is substituted with any one or more of fluorine,hydroxy, cyano, amino, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkyl,carboxyl, and C₃₋₇ heterocycloalkyl; wherein,

R⁶ is any one of hydroxy, amino, carboxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl,C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇cycloalkylamino, C₃₋₇ heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl.

R⁷ is any one of hydrogen, deuterium, and C₁₋₆ alkyl;

R⁸ is any one of hydrogen, deuterium, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, andC₃₋₇ heterocycloalkyl.

Preferably, R is any one of hydrogen, methyl, ethyl, and isopropyl;

R¹ is any one of hydrogen, deuterium, fluorine, chlorine, bromine,methyl, ethyl, isopropyl, and tert-butyl;

R² is any one of hydrogen, deuterium, fluorine, chlorine, bromine,methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl, cyclopropyl, cyclopentyl, methoxy, ethoxy, and isopropoxy;

Ar is phenyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, cyano, methyl, ethyl, trifluoromethyl,trifluoromethylmethyl, hydroxymethyl, cyanomethyl, benzyl,pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,morpholinylethyl, methoxy, and methylamino; or pyrazolyl substitutedwith any one or more of deuterium, fluorine, chlorine, bromine, hydroxy,cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, benzyl,pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, carboxypropyl, morpholinylethyl, methoxy, methylamino,oxetanyl, piperidyl, and ethoxycarbonylethyl; or pyridinyl substitutedwith any one or more of deuterium, fluorine, chlorine, bromine, hydroxy,amino, cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl,methoxymethyl, methoxyethyl, methoxypropyl, methylaminoethyl,morpholinylethyl, morpholinyl, piperidyl, piperazinyl, pyrrolidinyl,azetidinyl, methoxy, methoxyethoxy, methylamino, dimethylamino,cyclopropylamino, cyclobutylamino, cyclopropylmethylamino,4-hydroxypiperidyl, 4-methylpiperazinyl, 4-ethylpiperazinyl,4-acetylpiperazinyl, ethoxycarbonylethyl, acetylamino, andcarboxymethylamino; or 1, 2, 4-triazolyl substituted with any one ormore of deuterium, fluorine, chlorine, bromine, hydroxy, amino, methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,difluoromethyl, trifluoromethyl, trifluoromethylmethyl, hydroxymethyl,hydroxyethyl, hydroxypropyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, and morpholinylethyl; or thiazolyl substituted with anyone or more of deuterium, fluorine, chlorine, bromine, hydroxy, amino,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, aminomethyl,methoxymethyl, methoxyethyl, methoxypropyl, methylaminoethyl,cyclopropylmethyl, carboxymethyl, carboxyethyl, carboxypropyl,morpholinylethyl, oxetanyl, piperidyl, morpholinyl, piperazinyl,4-hydroxypiperidyl, 4-methylpiperazinyl, and ethoxycarbonylethyl; orpyrimidyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, amino, cyano, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxyethyl, cyanomethyl,aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, azetidinyl,piperidyl, piperazinyl, methoxy, methylamino, dimethylamino,cyclopropylamino, cyclopropylmethylamino, 4-ethylpiperazinyl,ethoxycarbonylethyl, 4-carboxypiperidyl, cyclobutylamino,3-carboxypyrrolidinyl, and carboxymethylamino; or pyridin-2(1H)-ketosubstituted with any one or more of deuterium, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxyethyl, cyanomethyl,aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, piperidyl,piperazinyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, andethoxycarbonylpropyl;

R³ is any one of hydrogen, deuterium, fluorine, chlorine, bromine,cyano, methyl, ethyl, and cyclopropyl;

R⁴ is any one of hydrogen, deuterium, methyl, and ethyl;

R⁵ is any one of hydrogen, deuterium, methyl, ethyl, isopropyl, butyl,sec-butyl, isobutyl, tert-butyl, and cyclopropyl.

Preferably, R is any one of hydrogen and C₁₋₆ alkyl;

R¹ is any one of hydrogen, deuterium, halogen, and C₁₋₆ alkoxy;

R² is any one of hydrogen, deuterium, halogen, C₁₋₆ alkylamino, and C₁₋₆alkoxy;

Ar is any one of phenyl, pyrazolyl, pyridinyl, thiazolyl, 1, 2,4-triazolyl, pyrimidinyl, and pyridin-2(1H)-keto;

R³ is any one of hydrogen, deuterium, and halogen;

R⁴ is hydrogen or deuterium;

R⁵ is any one of hydrogen, deuterium, C₁₋₆ alkyl, C₁₋₆ alkyl substitutedwith at least one fluorine, and C₃₋₇ cycloalkyl.

Preferably, Ar is substituted with any one or more of deuterium,halogen, hydroxy, cyano, amino, C₁₋₆ alkyl, a substituted C₁₋₆ alkyl,C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy C₁₋₆ alkoxy, C₁₋₆alkylamino, di-C₁₋₆ alkylamino, C₃₋₇ cycloalkylamino, C₃₋₇heterocycloalkylamino, C₃₋₇ cycloalkyl C₁₋₆ alkylamino, carboxyl C₁₋₆alkylamino, —C₃₋₇ heterocycloalkyl-R⁶, —C(═O)—R⁶, —C₁₋₆ alkyl-C(═O)—R⁶,—S(═O)₂—R⁶, —C₁₋₆ alkyl-S(═O)₂—R⁶, and —N(R⁷)—C(═O)—R⁸, wherein thesubstituted C₁₋₆ alkyl is substituted with any one or more of fluorine,hydroxy, cyano, amino, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkyl,carboxyl, and C₃₋₇ heterocycloalkyl; wherein,

R⁶ is any one of hydroxy, amino, carboxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl,C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇cycloalkylamino, C₃₋₇ heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl;

R⁷ is any one of hydrogen, deuterium, and C₁₋₆ alkyl;

R⁸ is any one of hydrogen, deuterium, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, andC₃₋₇ heterocycloalkyl.

Preferably, R is any one of hydrogen, methyl, ethyl, and isopropyl;

R¹ is any one of hydrogen, deuterium, fluorine, chlorine, bromine,methoxy, ethoxy, and isopropoxy;

R² is any one of hydrogen, deuterium, fluorine, chlorine, bromine,methylamino, ethylamino, methoxy, ethoxy, and isopropoxy;

Ar is phenyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, cyano, methyl, ethyl, trifluoromethyl,trifluoromethylmethyl, hydroxymethyl, cyanomethyl, benzyl,pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,morpholinylethyl, methoxy, and methylamino; or pyrazolyl substitutedwith any one or more of deuterium, fluorine, chlorine, bromine, hydroxy,cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, benzyl,pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, carboxypropyl, morpholinylethyl, methoxy, methylamino,oxetanyl, piperidyl, and ethoxycarbonylethyl; or pyridinyl substitutedwith any one or more of deuterium, fluorine, chlorine, bromine, hydroxy,amino, cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl,methoxymethyl, methoxyethyl, methoxypropyl, methylaminoethyl,morpholinylethyl, morpholinyl, piperidyl, piperazinyl, pyrrolidinyl,azetidinyl, methoxy, methoxyethoxy, methylamino, dimethylamino,cyclopropylamino, cyclobutylamino, cyclopropylmethylamino,4-hydroxypiperidyl, 4-methylpiperazinyl, 4-ethylpiperazinyl,4-acetylpiperazinyl, ethoxycarbonylethyl, acetylamino, andcarboxymethylamino; or 1, 2, 4-triazolyl substituted with any one ormore of deuterium, fluorine, chlorine, bromine, hydroxy, amino, methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,difluoromethyl, trifluoromethyl, trifluoromethylmethyl, hydroxymethyl,hydroxyethyl, hydroxypropyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, and morpholinylethyl; or thiazolyl substituted with anyone or more of deuterium, fluorine, chlorine, bromine, hydroxy, amino,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, aminomethyl,methoxymethyl, methoxyethyl, methoxypropyl, methylaminoethyl,cyclopropylmethyl, carboxymethyl, carboxyethyl, carboxypropyl,morpholinylethyl, oxetanyl, piperidyl, morpholinyl, piperazinyl,4-hydroxypiperidyl, 4-methylpiperazinyl, and ethoxycarbonylethyl; orpyrimidyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, amino, cyano, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxyethyl, cyanomethyl,aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, azetidinyl,piperidyl, piperazinyl, methoxy, methylamino, dimethylamino,cyclopropylamino, cyclopropylmethylamino, 4-ethylpiperazinyl,ethoxycarbonylethyl, 4-carboxypiperidyl, cyclobutylamino,3-carboxypyrrolidinyl, and carboxymethylamino; or pyridin-2(1H)-ketosubstituted with any one or more of deuterium, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxyethyl, cyanomethyl,aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, piperidyl,piperazinyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, andethoxycarbonylpropyl;

R³ is any one of hydrogen, deuterium, fluorine, chlorine, and bromine;

R⁴ is hydrogen or deuterium;

R⁵ is any one of hydrogen, deuterium, methyl, ethyl, isopropyl, butyl,sec-butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl,and cyclopropyl.

Preferably, R is any one of hydrogen, methyl, and ethyl.

Preferably, R¹ is hydrogen or deuterium.

Preferably, R² is any one of hydrogen, deuterium, fluorine, chlorine,bromine, methylamino, ethylamino, methoxy, ethoxy, and isopropoxy.

Preferably, Ar is phenyl substituted with any one or more of deuterium,halogen, hydroxy, cyano, C₁₋₆ alkyl, a substituted C₁₋₆ alkyl, C₁₋₆alkoxy, and C₁₋₆ alkylamino, wherein the substituted C₁₋₆ alkyl issubstituted with any one or more of fluorine, hydroxy, cyano, aryl,heteroaryl, amino, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkyl,carboxyl, and C₃₋₇ heterocycloalkyl.

Preferably, Ar is phenyl substituted with any one or more of deuterium,fluorine, chlorine, bromine, hydroxy, cyano, methyl, ethyl,trifluoromethyl, trifluoromethylmethyl, hydroxymethyl, cyanomethyl,benzyl, pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,morpholinylethyl, methoxy, and methylamino.

Preferably, Ar is pyrazolyl substituted with any one or more ofdeuterium, halogen, hydroxy, cyano, C₁₋₆ alkyl, a substituted C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇ heterocycloalkyl, and —C₁₋₆alkyl-C(═O)—R⁶, wherein the substituted C₁₋₆ alkyl is substituted withany one or more of fluorine, hydroxy, cyano, aryl, heteroaryl, amino,C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkyl, carboxyl, and C₃₋₇heterocycloalkyl; wherein,

R⁶ is any one of hydroxy, amino, carboxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl,C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇cycloalkylamino, C₃₋₇ heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl.

Preferably, Ar is pyrazolyl substituted with any one or more ofdeuterium, fluorine, chlorine, bromine, hydroxy, cyano, methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,difluoromethyl, trifluoromethyl, trifluoromethylmethyl, hydroxymethyl,hydroxyethyl, hydroxypropyl, cyanomethyl, benzyl, pyrazolylmethyl,aminomethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, methoxy, methylamino, oxetanyl,piperidyl, and ethoxycarbonylethyl.

Preferably, Ar is pyridinyl substituted with any one or more ofdeuterium, halogen, hydroxy, amino, cyano, C₁₋₆ alkyl, a substitutedC₁₋₆ alkyl, and C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy C₁₋₆alkoxy, C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₃₋₇ cycloalkylamino, C₃₋₇cycloalkyl C₁₋₆ alkylamino, carboxyl C₁₋₆ alkylamino, —C₃₋₇heterocycloalkyl-R⁶, —C₁₋₆ alkyl-C(═O)—R⁶, and —N(R⁷)—C(═O)—R⁸, whereinthe substituted C₁₋₆ alkyl is substituted with any one or more offluorine, C₁₋₆ alkoxy, C₁₋₆ alkylamino, and C₃₋₇ heterocycloalkyl;wherein,

R⁶ is any one of hydroxy, amino, carboxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl,C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇cycloalkylamino, C₃₋₇ heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl.

R⁷ is any one of hydrogen, deuterium, C₁₋₆ alkyl, and C₃₋₇ cycloalkyl;

R⁸ is any one of hydrogen, deuterium, C₁₋₆ alkyl, aryl, heteroaryl, C₃₋₇cycloalkyl, aryl C₁₋₆ alkyl, heteroaryl C₁₋₆ alkyl, and C₃₋₇heterocycloalkyl.

Preferably, Ar is pyridinyl substituted with any one or more ofdeuterium, fluorine, chlorine, bromine, hydroxy, amino, cyano, methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,trifluoromethyl, trifluoromethylmethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, morpholinylethyl, morpholinyl,piperidyl, piperazinyl, pyrrolidinyl, azetidinyl, methoxy,methoxyethoxy, methylamino, dimethylamino, cyclopropylamino,cyclobutylamino, cyclopropylmethylamino, 4-hydroxypiperidyl,4-methylpiperazinyl, 4-ethylpiperazinyl, 4-acetylpiperazinyl,ethoxycarbonylethyl, acetylamino, and carboxymethylamino.

Preferably, Ar is 1, 2, 4-triazolyl substituted with any one or more ofdeuterium, halogen, hydroxy, amino, C₁₋₆ alkyl, and C₁₋₆ alkylsubstituted with any one or more of fluorine, hydroxy, amino, C₁₋₆alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkyl, carboxyl, and C₃₋₇heterocycloalkyl.

Preferably, Ar is 1, 2, 4-triazolyl substituted with any one or more ofdeuterium, fluorine, chlorine, bromine, hydroxy, amino, methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,difluoromethyl, trifluoromethyl, trifluoromethylmethyl, hydroxymethyl,hydroxyethyl, hydroxypropyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, and morpholinylethyl.

Preferably, Ar is thiazolyl substituted with any one or more ofdeuterium, halogen, hydroxy, amino, C₁₋₆ alkyl, a substituted C₁₋₆alkyl, C₃₋₇ heterocycloalkyl, —C₃₋₇ heterocycloalkyl-R⁶, and —C₁₋₆alkyl-C(═O)—R⁶, wherein the substituted C₁₋₆ alkyl is substituted withany one or more of fluorine, hydroxy, cyano, amino, C₁₋₆ alkoxy, C₁₋₆alkylamino, C₃₋₇ cycloalkyl, carboxyl, and C₃₋₇ heterocycloalkyl;wherein,

R⁶ is any one of hydroxy, amino, carboxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl,C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇cycloalkylamino, C₃₋₇ heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl.

Preferably, Ar is thiazolyl substituted with any one or more ofdeuterium, fluorine, chlorine, bromine, hydroxy, amino, methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,difluoromethyl, trifluoromethyl, trifluoromethylmethyl, hydroxymethyl,hydroxyethyl, hydroxypropyl, cyanomethyl, aminomethyl, methoxymethyl,methoxyethyl, methoxypropyl, methylaminoethyl, cyclopropylmethyl,carboxymethyl, carboxyethyl, carboxypropyl, morpholinylethyl, oxetanyl,piperidyl, morpholinyl, piperazinyl, 4-hydroxypiperidyl,4-methylpiperazinyl, and ethoxycarbonylethyl.

Preferably, Ar is pyrimidyl substituted with any one or more ofdeuterium, halogen, hydroxy, amino, cyano, C₁₋₆ alkyl, a substitutedC₁₋₆ alkyl, C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, di-C₁₋₆alkylamino, C₃₋₇ cycloalkylamino, C₃₋₇ cycloalkyl C₁₋₆ alkylamino,carboxyl C₁₋₆ alkylamino, —C₃₋₇ heterocycloalkyl-R⁶, and —C₁₋₆alkyl-C(═O)—R⁶, wherein the substituted C₁₋₆ alkyl is substituted withany one or more of fluorine, hydroxy, cyano, amino, C₁₋₆ alkoxy, C₁₋₆alkylamino, C₃₋₇ cycloalkyl, carboxyl, and C₃₋₇ heterocycloalkyl;wherein,

R⁶ is any one of hydroxy, amino, carboxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl,C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇cycloalkylamino, C₃₋₇ heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl.

Preferably, Ar is pyrimidyl substituted with any one or more ofdeuterium, fluorine, chlorine, bromine, hydroxy, amino, cyano, methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,difluoromethyl, trifluoromethyl, trifluoromethylmethyl, hydroxyethyl,cyanomethyl, aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, azetidinyl,piperidyl, piperazinyl, methoxy, methylamino, dimethylamino,cyclopropylamino, cyclopropylmethylamino, 4-ethylpiperazinyl,ethoxycarbonylethyl, 4-carboxypiperidyl, cyclobutylamino,3-carboxypyrrolidinyl, and carboxymethylamino.

Preferably, Ar is pyridin-2(1H)-keto substituted with any one or more ofdeuterium, C₁₋₆ alkyl, a substituted C₁₋₆ alkyl, C₃₋₇ heterocycloalkyl,and —C₁₋₆ alkyl-C(═O)—R⁶, wherein the substituted C₁₋₆ alkyl issubstituted with any one or more of fluorine, hydroxy, cyano, amino,C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkyl, carboxyl, and C₃₋₇heterocycloalkyl; wherein,

R⁶ is any one of hydroxy, amino, carboxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl,C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇cycloalkylamino, C₃₋₇ heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl.

Preferably, Ar is pyridin-2(1H)-keto substituted with any one or more ofdeuterium, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxyethyl, cyanomethyl, aminoethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, carboxypropyl, morpholinylethyl, morpholinyl,pyrrolidinyl, piperidyl, piperazinyl, ethoxycarbonylmethyl,ethoxycarbonylethyl, and ethoxycarbonylpropyl.

Preferably, R³ is hydrogen or deuterium.

Preferably, R⁴ is hydrogen or deuterium.

Preferably, R⁵ is any one of hydrogen, deuterium, methyl, ethyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, trifluoromethyl,trifluoromethylmethyl, and cyclopropyl.

Preferably, particular compounds of formula I according to the inventionare the following:

-   6-isopropyl-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-isopropyl-10-methoxy-2-oxo-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-isopropyl-10-methoxy-9-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   9-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   9-(1-isobutyl-1H-pyrazol-4-yl)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-isopropyl-10-methoxy-2-oxo-9-(1-propyl-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-isopropyl-10-methoxy-9-(6-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-2-oxo-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-9-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-9-(1-methyl-1H-pyrazol-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(1-(difluoromethyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(1,3-dimethyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-9-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-2-oxo-9-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid hydrochloride;-   6-(tert-butyl)-9-(1-isopropyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(1,4-dimethyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(1-(carboxymethyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   ethyl    6-(tert-butyl)-9-(1-(3-ethoxy-3-oxopropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate;-   6-(tert-butyl)-9-(1-(2-carboxyethyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(1-(3-ethoxy-3-oxopropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(1-(3-carboxypropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-9-(3-methyl-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(1-(1-carboxyethyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(1-(2-carboxypropan-2-yl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-9-(2-methylthiazol-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-1,2,4-triazol-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(1-(carboxymethyl)-1H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(4-(3-hydroxypropyl)-4H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(1-(3-hydroxypropyl)-1H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-2-oxo-9-phenyl-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(4-ethylphenyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-9-(4-methoxyphenyl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-9-(3-methoxyphenyl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-9-(6-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-9-(2-methylpyridin-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-9-(2-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-9-(6-morpholinopyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-2-oxo-9-(6-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-9-(6-(2-methoxyethoxy)pyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(6-(dimethylamino)pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-2-oxo-9-(6-(pyrrolidin-1-yl)pyridin-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-2-oxo-9-(6-(piperazin-1-yl)pyridin-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   9-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-9-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(6-fluoro-4-methylpyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(6-fluoropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   9-(6-(azetidin-1-yl)pyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(6-((cyclopropylmethyl)amino)pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   9-(6-(azetidin-1-yl)-4-methylpyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   9-(6-aminopyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   ethyl    6-(tert-butyl)-10-methoxy-9-(6-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate;-   6-(tert-butyl)-9-(6-(cyclobutylamino)pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   9-(6-acetamidopyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-9-(2-methylpyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-2-oxo-9-(2-(pyrrolidin-1-yl)pyrimidin-5-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-9-(2-(methylamino)pyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(2-(dimethylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-9-(2-morpholinopyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(2-(cyclopropylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   9-(2-aminopyrimidin-5-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-10-methoxy-9-(2-methoxypyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(2-((cyclopropylmethyl)amino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(2-chloropyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   9-(2-(azetidin-1-yl)pyrimidin-5-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   ethyl    6-(tert-butyl)-9-(1-(1-ethoxy-2-methyl-1-oxopropan-2-yl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate;-   ethyl    6-(tert-butyl)-9-(1-(2-ethoxy-2-oxoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate;-   ethyl    6-(tert-butyl)-9-(1-(3-ethoxy-3-oxopropyl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate;-   6-(tert-butyl)-9-(2-(4-carboxypiperidin-1-yl)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   ethyl    6-(tert-butyl)-9-(1-(1-ethoxy-1-oxopropan-2-yl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate;-   ethyl    6-(tert-butyl)-9-(1-(4-ethoxy-4-oxobutyl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate;-   6-(tert-butyl)-9-(2-(cyclobutylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(2-(3-carboxypyrrolidin-1-yl)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic    acid;-   6-(tert-butyl)-9-(2-((carboxymethyl)amino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-di    hydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid.

Preferably, the compounds described herein are made into correspondingenantiomers, diastereoisomers, solvates, hydrates, prodrugs, stableisotope derivatives and pharmaceutically acceptable salts.

Preferably, the compounds described herein are made into correspondingpharmaceutically acceptable derivatives, wherein the derivative is anyone of a prodrug, a salt, an ester, an amide, a salt of the ester, asalt of the amide, and a metabolite.

Preferably, the compounds described herein are made into correspondingsalts, wherein acid used to form the salt is selected from:

hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid,sulfuric acid or phosphoric acid, acetic acid, oxalic acid, maleic acid,fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid,salicylic acid, succinic acid, citric acid, lactic acid, propionic acid,benzoic acid, p-toluenesulfonic acid, and malic acid.

Base used to form the salt is selected from:

lithium hydroxide, sodium hydroxide, potassium hydroxide, sodiumcarbonate, sodium bicarbonate, potassium carbonate, potassiumbicarbonate, magnesium carbonate, calcium carbonate, ammonia liquor,triethylamine, and tetrabutylammonium hydroxide.

Preferably, the compounds described herein are made into anycomposition, wherein the composition also comprises:

-   -   a pharmaceutically acceptable carrier;    -   an auxiliary agent; and/or    -   an excipient.

Preferably, the compounds described herein are made into dosage form,wherein the dosage form is any one of a tablet, a capsule, an injection,a granule, a pulvis, a suppository, a pill, a cream, a paste, a gel, apowder, an oral solution, an inhalation, a suspension, a dry suspension,a patch, and a lotion.

Preferably, the compounds described herein are made into compositioncomprising at least one of the following substances:

an HBV polymerase inhibitor, interferon α-2a, interferon α-2b, apegylated interferon α-2a, ribavirin, an HBV preventive vaccine, an HBVtherapeutic vaccine, an HBV capsid inhibitor, an RNA replicationinhibitor of HBV, an siRNA, an inhibitor of HBsAg generation orsecretion, an HBV antibody, and a TLR7 agonist.

Preferably, the compounds described herein are used for medical use.

Preferably, the compounds described herein are used to prevent or treathepatitis B virus infection.

Compounds described in the invention can be used to prevent or treathepatitis B virus infection.

DETAILED DESCRIPTION OF THE INVENTION

For a clearer description of the contents of the present invention, allterms involved in this application are defined as follows:

As used herein, the term “C₁₋₆ alkyl” alone or in combination signifiesa saturated, linear or branched chain alkyl group containing 1 to 6carbon atoms, particularly 1 to 4 carbon atoms, including methyl, ethyl,propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl,2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl,3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, or3,3-dimethyl-2-butyl and the like. Particular, “C₁₋₆ alkyl” is any oneof methyl, ethyl, isopropyl, tert-butyl.

As used herein, the term “C₃₋₇ cycloalkyl” alone or in combinationsignifies a saturated carbon ring containing from 3 to 7 carbon atoms,particularly from 3 to 6 carbon atoms, including cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.Particular, “C₃₋₇ cycloalkyl” groups are cyclopropyl, cyclopentyl andcyclohexyl.

As used herein, the term “amino” alone or in combination, refers toprimary (—NH₂), secondary (—NH—) or tertiary amino

As used herein, the term “C₁₋₆ alkylamino” alone or in combination,refers to amino group as defined above wherein at least one of thehydrogen atoms of the amino group is replaced by a C₁₋₆ alkyl group,wherein the “C₁₋₆ alkyl” is as defined above. “C₁₋₆ alkylamino” groupsinclude methylamino, ethylamino, propylamino, isopropylamino,n-butylamino, iso-butylamino, sec-butylamino, tert-butylamino,n-pentylamino, 2-pentylamino, 3-pentylamino, 2-methyl-2-butylamino,3-methyl-2-butylamino, 3-methyl-1-butylamino, 2-methyl-1-butylamino,n-hexylamino, 2-hexylamino, 3-hexylamino, 2-methyl-2-pentylamino,3-methyl-2-pentylamino, 4-methyl-2-pentylamino, 3-methyl-3-pentylamino,2-methyl-3-pentylamino, 2,3-dimethyl-2-butylamino, or3,3-dimethyl-2-butylamino and the like. Particular, “C₁₋₆ alkylamino”groups are methylamino, ethylamino, isopropylamino, tert-butylamino andthe like.

As used herein, the term “C₁₋₆ alkoxyl” alone or in combination, refersto a group of C₁₋₆ alkyl-O—, wherein the “C₁₋₆ alkyl” is as definedabove.

As used herein, the term “halogen” alone or in combination, refers tofluorine, chlorine, bromine, or iodine. Halogen is particularlyfluorine, chlorine or bromine.

As used herein, the term “heterocycloalkyl” refers to a saturated orpartly unsaturated monocyclic or bicyclic non-aromatic ring (containing1 to 2 double bonds) which can comprise atoms selected from nitrogen,oxygen and/or sulfur. In this invention, the number of carbon atoms in“heterocycloalkyl” group is 2 to 11, and the number of hetero atoms ispreferably 1, 2, 3 or 4, and the nitrogen, carbon or sulfur atom in the“heterocycloalkyl” group can be optionally oxidated. The hydrogen atomon the “heterocycloalkyl” group is independently optionally substitutedby any one or more of substituents described herein. “Heterocycloalkyl”can be attached to the parent molecule through any ring atom on thering.

As used herein, the term “C₃₋₇ heterocycloalkyl” refers to a monocyclicheterocycloalkyl including from 3 to 7 carbon atoms and hetero atoms.For example, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl,piperazinyl, thiomorpholyl, tetrahydropyranyl, 1,1-dioxathiomorpholinyl.

As used herein, the term “C₃₋₇ cycloalkylamino” alone or in combination,refers to amino group as defined above wherein at least one of thehydrogen atoms of the amino group is replaced by a C₃₋₇ cycloalkylgroup, wherein the “C₃₋₇ cycloalkyl” is as defined above.

As used herein, the term “C₃₋₇ heterocycloalkylamino” alone or incombination, refers to amino group as defined above wherein at least oneof the hydrogen atoms of the amino group is replaced by a C₃₋₇heterocycloalkyl group, wherein the “C₃₋₇ heterocycloalkyl” is asdefined above.

As used herein, the term “Aryl” refers to any stable 6-10 memberedmonocyclic or bicyclic aromatic group including phenyl, naphthyl,tetrahydronaphthyl, indanyl or biphenyl. The hydrogen atom on the “aryl”is, independently, optionally substituted by any one of substituentsdescribed herein.

As used herein, the term “heteroaryl” refers to an aromatic ring formedby the replacement of a carbon atom on the ring with at least oneheteroatom selected from sulfur, oxygen or nitrogen, which can be a 5-7membered monocyclic ring or 7-12 bicyclic group. In this invention, thenumber of hetero atoms in the heteroaryl group is preferably 1, 2, 3 or4, for example thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,pyridine-2(1H)-one, pyridin-4(1H)-keto, pyrrolyl, pyrazolyl, thiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl,oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, naphthyl, benzothienyl,indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolyl,isoquinolyl, quinazolinyl and the like. The hydrogen atom on the“heteroaryl” is, independently, optionally substituted by any one ofsubstituents described herein.

As used herein, the term “Aryl C₁₋₆ alkyl” refers to a group of C₁₋₆alkyl as defined above, wherein at least one of the hydrogen atoms onthe C₁₋₆ alkyl group is replaced by at least one aryl group, wherein the“aryl” is as defined above.

As used herein, the term “Heteroaryl C₁₋₆ alkyl” refers to a group ofC₁₋₆ alkyl as defined above, wherein at least one of the hydrogen atomson the C₁₋₆ alkyl group is replaced by at least one heteroaryl group,wherein the “heteroaryl” is as defined above.

As used herein, the term “cyano” alone or in combination, refers to —CN.

As used herein, the term “carboxyl” alone or in combination, refers to—COOH.

As used herein, the term “hydroxyl” alone or in combination, refers to—OH.

As used herein, the term “isomer” encompasses all isomeric formsincluding enantiomers, diastereomers, and geometric isomers includingcis and trans isomers. Thus, a single stereochemical isomer of acompound designed in this invention, or an enantiomer, diastereomer, ormixture of geometric isomers (or cis and trans isomers thereof) thereof,is belonging to the scope of this invention

As used herein, the term “pharmaceutically acceptable salts” refers tothat the compounds of the invention exist in the form of theirpharmaceutically acceptable salts, including both acid and base additionsalts. Pharmaceutically acceptable salts are described by S. M. Berge inJ. Pharmaceutical Sciences (Vol. 66: Page 1-19, 1977). In thisinvention, a pharmaceutically acceptable non-toxic acid addition saltmeans a salt of a compound in this invention with an organic orinorganic acid including, but not limited to, hydrochloric acid,sulfuric acid, hydrobromic acid, and hydroiodic acid, phosphoric acid,nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid,fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid,salicylic acid, succinic acid, citric acid, lactic acid, propionic acid,benzoic acid, p-toluenesulfonic acid, malic acid and the like. Apharmaceutically acceptable non-toxic base addition salt means a salt ofa compound of the invention with an organic or inorganic base, includingbut not limited to an alkali metal salts such as a lithium, sodium orpotassium salts; an alkaline earth metal salts such as calcium or amagnesium salts; an organic base salts, for example, an ammonium salt oran N+(C₁₋₆ alkyl)₄ salt formed by an organic base containing an N group.

As used herein, the term “solvate” refers to an association compound ofone or more solvent molecules with a compound in this invention.Solvents include, but are not limited to, water, methanol, ethanol,isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide,dimethyl sulfoxide, and the like. “Pharmaceutically acceptable salts”can be synthesized by general chemical methods.

As used herein, the term “hydrate” refers to an association compound ofwater with a compound in this invention.

As used herein, the term “prodrug” refers to a chemical derivative of acompound in the invention, which can be converted into a compoundrepresented by the formula I by chemical reaction in vivo.

As used herein, the term “isotopic derivative” refers to an isotopederivative obtained by substituting a hydrogen atom of the formula Iwith 1-6 deuterium atoms, and an isotope derivative obtained bysubstituting a carbon atom of the formula I with 1 to 3 carbon-14 atoms.

The terms involved in this invention has been defined above, and thoseskilled in the art can also understand the above terms in combinationwith current technology. The following description based on the contentof this invention and the definition of the terms are further described.

A compound of general formula I:

wherein:

R is any one of hydrogen and C₁₋₆ alkyl; Preferably, R is any one ofhydrogen, methyl and ethyl.

R¹ is any one of hydrogen, deuterium, halogen, C₁₋₆ alkyl, C₁₋₆alkylamino, and C₁₋₆ alkoxyl; Preferably, R is hydrogen or deuterium.

R² is any one of hydrogen, deuterium, halogen, C₁₋₆ alkyl, C₁₋₆ alkylsubstituted with at least one fluorine, C₃₋₇ cycloalkyl, C₁₋₆alkylamino, C₁₋₆ alkoxy, and heterocycloalkyl; Preferably, R² is any oneof hydrogen, deuterium, halogen, C₁₋₆ alkoxyl; More preferably, R² isC₁₋₆ alkoxyl.

Ar is any one of phenyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyridin-2(1H)-keto, pyridin-4(1H)-keto, pyrrolyl,pyrazolyl, thiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, imidazolyl,tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl,oxadiazolyl, naphthyl, benzothiophenyl, indolyl, benzimidazolyl,benzothiazolyl, benzofuryl, quinolyl, isoquinolyl, and quinazolinyl; Asan variant, Ar is substituted with any one or more of deuterium,halogen, hydroxy, amino, cyano, C₁₋₆ alkyl, a substituted C₁₋₆ alkyl,C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy C₁₋₆ alkoxy, C₁₋₆alkylamino, di-C₁₋₆ alkylamino, C₃₋₇ cycloalkylamino, C₃₋₇heterocycloalkylamino, C₃₋₇ cycloalkyl C₁₋₆ alkylamino, carboxyl C₁₋₆alkylamino, —C₃₋₇ heterocycloalkyl-R⁶, —C(═O)—R⁶, —C₁₋₆ alkyl-C(═O)—R⁶,—S(═O)₂—R⁶, —C₁₋₆ alkyl-S(═O)₂—R⁶, —N(R⁷)—C(═O)—R⁸, —C₁₋₆alkylamino-C(═O)—C₁₋₆ alkyl, and —C₁₋₆ alkylamino-C(═O)-amino C₁₋₆alkyl, wherein the substituted C₁₋₆ alkyl is substituted with any one ormore of fluorine, hydroxy, cyano, aryl, heteroaryl, amino, C₁₋₆ alkoxy,C₁₋₆ alkylamino, C₃₋₇ cycloalkyl, carboxyl, and C₃₋₇ heterocycloalkyl;wherein, R⁶ is any one of hydroxy, amino, carboxyl, C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇cycloalkylamino, C₃₋₇ heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl; R⁷is any one of hydrogen, deuterium, C₁₋₆ alkyl, and C₃₋₇ cycloalkyl; R⁸is any one of hydrogen, deuterium, C₁₋₆ alkyl, aryl, heteroaryl, C₃₋₇cycloalkyl, aryl C₁₋₆ alkyl, heteroaryl C₁₋₆ alkyl, and C₃₋₇heterocycloalkyl. Preferably, Ar is any one of phenyl, thienyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, pyridine-2(1H)-keto,pyridin-4(1H)-keto, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl,isoxazolyl, thiadiazolyl, and oxadiazolyl.

R³ is any one of hydrogen, deuterium, halogen, cyano, C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy, and heterocycloalkyl;Preferably, R³ is hydrogen or deuterium.

R⁴ is any one of hydrogen, deuterium, and C₁₋₆ alkyl; Preferably, R⁴ ishydrogen or deuterium.

R⁵ is any one of hydrogen, deuterium, C₁₋₆ alkyl, C₁₋₆ alkyl substitutedwith at least one fluorine, and C₃₋₇ cycloalkyl. Preferably, R⁵ is anyone of hydrogen, deuterium, methyl, ethyl, isopropyl, butyl, sec-butyl,isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl, andcyclopropyl. More preferably, R⁵ is any one of isopropyl, tert-butyl andcyclopropyl.

A compound as the first embodiment of formula I, wherein:

R is any one of hydrogen, methyl, ethyl, propyl, isopropyl, andtert-butyl;

R¹ is any one of hydrogen, deuterium, fluorine, chlorine, bromine,methyl, ethyl, isopropyl, tert-butyl, methylamino, ethylamino, methoxy,ethoxy, and isopropoxy.

R² is any one of hydrogen, deuterium, fluorine, chlorine, bromine,methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl,trifluoromethylmethyl, cyclopropyl, cyclopentyl, methylamino,ethylamino, methoxy, ethoxy, isopropoxy, pyrrolidinyl, and morpholinyl.

Ar is phenyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, cyano, methyl, ethyl, trifluoromethyl,trifluoromethylmethyl, hydroxymethyl, cyanomethyl, benzyl,pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,morpholinylethyl, methoxy, and methylamino; or pyrazolyl substitutedwith any one or more of deuterium, fluorine, chlorine, bromine, hydroxy,cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, benzyl,pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, carboxypropyl, morpholinylethyl, methoxy, methylamino,oxetanyl, piperidyl, and ethoxycarbonylethyl; or pyridinyl substitutedwith any one or more of deuterium, fluorine, chlorine, bromine, hydroxy,amino, cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl,methoxymethyl, methoxyethyl, methoxypropyl, methylaminoethyl,morpholinylethyl, morpholinyl, piperidyl, piperazinyl, pyrrolidinyl,azetidinyl, methoxy, methoxyethoxy, methylamino, dimethylamino,cyclopropylamino, cyclobutylamino, cyclopropylmethylamino,4-hydroxypiperidyl, 4-methylpiperazinyl, 4-ethylpiperazinyl,4-acetylpiperazinyl, ethoxycarbonylethyl, acetylamino, andcarboxymethylamino; or 1, 2, 4-triazolyl substituted with any one ormore of deuterium, fluorine, chlorine, bromine, hydroxy, amino, methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,difluoromethyl, trifluoromethyl, trifluoromethylmethyl, hydroxymethyl,hydroxyethyl, hydroxypropyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, and morpholinylethyl; or thiazolyl substituted with anyone or more of deuterium, fluorine, chlorine, bromine, hydroxy, amino,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, aminomethyl,methoxymethyl, methoxyethyl, methoxypropyl, methylaminoethyl,cyclopropylmethyl, carboxymethyl, carboxyethyl, carboxypropyl,morpholinylethyl, oxetanyl, piperidyl, morpholinyl, piperazinyl,4-hydroxypiperidyl, 4-methylpiperazinyl, and ethoxycarbonylethyl; orpyrimidyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, amino, cyano, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxyethyl, cyanomethyl,aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, azetidinyl,piperidyl, piperazinyl, methoxy, methylamino, dimethylamino,cyclopropylamino, cyclopropylmethylamino, 4-ethylpiperazinyl,ethoxycarbonylethyl, 4-carboxypiperidyl, cyclobutylamino,3-carboxypyrrolidinyl, and carboxymethylamino; or pyridin-2(1H)-ketosubstituted with any one or more of deuterium, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxyethyl, cyanomethyl,aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, piperidyl,piperazinyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, andethoxycarbonylpropyl;

R³ is any one of hydrogen, deuterium, fluorine, chlorine, bromine,methyl, ethyl, and cyano;

R⁴ is any one of hydrogen, deuterium, methyl, and ethyl;

R⁵ is any one of hydrogen, deuterium, methyl, ethyl, isopropyl, butyl,sec-butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl,and cyclopropyl.

A compound as the second embodiment of formula I, wherein:

R is any one of hydrogen and C₁₋₆ alkyl;

R¹ is any one of hydrogen, deuterium, halogen, and C₁₋₆ alkyl;

R² is any one of hydrogen, deuterium, halogen, C₁₋₆ alkyl, C₁₋₆ alkylsubstituted with at least one fluorine, C₃₋₇ cycloalkyl, and C₁₋₆alkoxy;

Ar is any one of phenyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyridin-2(1H)keto, pyridin-4(1H)-keto, pyrrolyl, pyrazolyl,thiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, imidazolyl, tetrazolyl,isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, and oxadiazolyl.Preferably, Ar is substituted with any one or more of deuterium,halogen, hydroxy, cyano, amino, C₁₋₆ alkyl, a substituted C₁₋₆ alkyl,C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy C₁₋₆ alkoxy, C₁₋₆alkylamino, di-C₁₋₆ alkylamino, C₃₋₇ cycloalkylamino, C₃₋₇heterocycloalkylamino, C₃₋₇ cycloalkyl C₁₋₆ alkylamino, carboxyl C₁₋₆alkylamino, —C₃₋₇ heterocycloalkyl-R⁶, —C(═O)—R⁶, —C₁₋₆ alkyl-C(═O)—R⁶,—S(═O)₂—R⁶, —C₁₋₆ alkyl-S(═O)₂—R⁶, and —N(R⁷)—C(═O)—R⁸, wherein thesubstituted C₁₋₆ alkyl is substituted with any one or more of fluorine,hydroxy, cyano, amino, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkyl,carboxyl, and C₃₋₇ heterocycloalkyl; wherein R⁶ is any one of hydroxy,amino, carboxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl,C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkylamino, C₃₋₇heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl.

R⁷ is any one of hydrogen, deuterium, and C₁₋₆ alkyl;

R⁸ is any one of hydrogen, deuterium, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, andC₃₋₇ heterocycloalkyl.

R³ is any one of hydrogen, deuterium, halogen, cyano, C₁₋₆ alkyl, andC₃₋₇ cycloalkyl;

R⁴ is any one of hydrogen, deuterium, and C₁₋₆ alkyl;

R⁵ is any one of hydrogen, deuterium, C₁₋₆ alkyl, C₁₋₆ alkyl substitutedwith at least one fluorine, and C₃₋₇ cycloalkyl.

A compound as the third embodiment of formula I, wherein:

R is any one of hydrogen, methyl, ethyl, and isopropyl;

R¹ is any one of hydrogen, deuterium, fluorine, chlorine, bromine,methyl, ethyl, isopropyl, and tert-butyl;

R² is any one of hydrogen, deuterium, fluorine, chlorine, bromine,methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl,trifluoromethylmethyl, cyclopropyl, cyclopentyl, methoxy, ethoxy, andisopropoxy;

Ar is phenyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, cyano, methyl, ethyl, trifluoromethyl,trifluoromethylmethyl, hydroxymethyl, cyanomethyl, benzyl,pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,morpholinylethyl, methoxy, and methylamino; or pyrazolyl substitutedwith any one or more of deuterium, fluorine, chlorine, bromine, hydroxy,cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, benzyl,pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, carboxypropyl, morpholinylethyl, methoxy, methylamino,oxetanyl, piperidyl, and ethoxycarbonylethyl; or pyridinyl substitutedwith any one or more of deuterium, fluorine, chlorine, bromine, hydroxy,amino, cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl,methoxymethyl, methoxyethyl, methoxypropyl, methylaminoethyl,morpholinylethyl, morpholinyl, piperidyl, piperazinyl, pyrrolidinyl,azetidinyl, methoxy, methoxyethoxy, methylamino, dimethylamino,cyclopropylamino, cyclobutylamino, cyclopropylmethylamino,4-hydroxypiperidyl, 4-methylpiperazinyl, 4-ethylpiperazinyl,4-acetylpiperazinyl, ethoxycarbonylethyl, acetylamino, andcarboxymethylamino; or 1, 2, 4-triazolyl substituted with any one ormore of deuterium, fluorine, chlorine, bromine, hydroxy, amino, methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,difluoromethyl, trifluoromethyl, trifluoromethylmethyl, hydroxymethyl,hydroxyethyl, hydroxypropyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, and morpholinylethyl; or thiazolyl substituted with anyone or more of deuterium, fluorine, chlorine, bromine, hydroxy, amino,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, aminomethyl,methoxymethyl, methoxyethyl, methoxypropyl, methylaminoethyl,cyclopropylmethyl, carboxymethyl, carboxyethyl, carboxypropyl,morpholinylethyl, oxetanyl, piperidyl, morpholinyl, piperazinyl,4-hydroxypiperidyl, 4-methylpiperazinyl, and ethoxycarbonylethyl; orpyrimidyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, amino, cyano, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxyethyl, cyanomethyl,aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, azetidinyl,piperidyl, piperazinyl, methoxy, methylamino, dimethylamino,cyclopropylamino, cyclopropylmethylamino, 4-ethylpiperazinyl,ethoxycarbonylethyl, 4-carboxypiperidyl, cyclobutylamino,3-carboxypyrrolidinyl, and carboxymethylamino; or pyridin-2(1H)-ketosubstituted with any one or more of deuterium, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxyethyl, cyanomethyl,aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, piperidyl,piperazinyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, andethoxycarbonylpropyl;

R³ is any one of hydrogen, deuterium, fluorine, chlorine, bromine,cyano, methyl, ethyl, and cyclopropyl;

R⁴ is any one of hydrogen, deuterium, methyl, and ethyl;

R⁵ is any one of hydrogen, deuterium, methyl, ethyl, isopropyl, butyl,sec-butyl, isobutyl, tert-butyl, and cyclopropyl.

A compound as the fourth embodiment of formula I, wherein:

R is any one of hydrogen and C₁₋₆ alkyl;

R¹ is any one of hydrogen, deuterium, halogen, and C₁₋₆ alkoxy;

R² is any one of hydrogen, deuterium, halogen, C₁₋₆ alkylamino, and C₁₋₆alkoxy;

Ar is any one of phenyl, pyrazolyl, pyridinyl, thiazolyl, 1, 2,4-triazolyl, pyrimidinyl, pyridin-2(1H)keto. Preferably, Ar issubstituted with any one or more of deuterium, halogen, hydroxy, cyano,amino, C₁₋₆ alkyl, a substituted C₁₋₆ alkyl, C₃₋₇ heterocycloalkyl, C₁₋₆alkoxy, C₁₋₆ alkoxy C₁₋₆ alkoxy, C₁₋₆ alkylamino, di-C₁₋₆ alkylamino,C₃₋₇ cycloalkylamino, C₃₋₇ heterocycloalkylamino, C₃₋₇ cycloalkyl C₁₋₆alkylamino, carboxyl C₁₋₆ alkylamino, —C₃₋₇ heterocycloalkyl-R⁶,—C(═O)—R⁶, —C₁₋₆ alkyl-C(═O)—R⁶, —S(═O)₂—R⁶, —C₁₋₆ alkyl-S(═O)₂—R⁶, and—N(R⁷)—C(═O)—R⁸, wherein the substituted C₁₋₆ alkyl is substituted withany one or more of fluorine, hydroxy, cyano, amino, C₁₋₆ alkoxy, C₁₋₆alkylamino, C₃₋₇ cycloalkyl, carboxyl, and C₃₋₇ heterocycloalkyl;wherein R⁶ is any one of hydroxy, amino, carboxyl, C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇cycloalkylamino, C₃₋₇ heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl;

R⁷ is any one of hydrogen, deuterium, and C₁₋₆ alkyl;

R⁸ is any one of hydrogen, deuterium, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, andC₃₋₇ heterocycloalkyl.

R³ is any one of hydrogen, deuterium, and halogen;

R⁴ is hydrogen or deuterium;

R⁵ is any one of hydrogen, deuterium, C₁₋₆ alkyl, C₁₋₆ alkyl substitutedwith at least one fluorine, and C₃₋₇ cycloalkyl.

A compound as the fifth embodiment of formula I, wherein:

R is any one of hydrogen, methyl, ethyl, and isopropyl;

R¹ is any one of hydrogen, deuterium, fluorine, chlorine, bromine,methoxy, ethoxy, and isopropoxy;

R² is any one of hydrogen, deuterium, fluorine, chlorine, bromine,methylamino, ethylamino, methoxy, ethoxy, and isopropoxy;

Ar is phenyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, cyano, methyl, ethyl, trifluoromethyl,trifluoromethylmethyl, hydroxymethyl, cyanomethyl, benzyl,pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,morpholinylethyl, methoxy, and methylamino; or pyrazolyl substitutedwith any one or more of deuterium, fluorine, chlorine, bromine, hydroxy,cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, benzyl,pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, carboxypropyl, morpholinylethyl, methoxy, methylamino,oxetanyl, piperidyl, and ethoxycarbonylethyl; or pyridinyl substitutedwith any one or more of deuterium, fluorine, chlorine, bromine, hydroxy,amino, cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl,methoxymethyl, methoxyethyl, methoxypropyl, methylaminoethyl,morpholinylethyl, morpholinyl, piperidyl, piperazinyl, pyrrolidinyl,azetidinyl, methoxy, methoxyethoxy, methylamino, dimethylamino,cyclopropylamino, cyclobutylamino, cyclopropylmethylamino,4-hydroxypiperidyl, 4-methylpiperazinyl, 4-ethylpiperazinyl,4-acetylpiperazinyl, ethoxycarbonylethyl, acetylamino, andcarboxymethylamino; or 1, 2, 4-triazolyl substituted with any one ormore of deuterium, fluorine, chlorine, bromine, hydroxy, amino, methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,difluoromethyl, trifluoromethyl, trifluoromethylmethyl, hydroxymethyl,hydroxyethyl, hydroxypropyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, and morpholinylethyl; or thiazolyl substituted with anyone or more of deuterium, fluorine, chlorine, bromine, hydroxy, amino,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, aminomethyl,methoxymethyl, methoxyethyl, methoxypropyl, methylaminoethyl,cyclopropylmethyl, carboxymethyl, carboxyethyl, carboxypropyl,morpholinylethyl, oxetanyl, piperidyl, morpholinyl, piperazinyl,4-hydroxypiperidyl, 4-methylpiperazinyl, and ethoxycarbonylethyl; orpyrimidyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, amino, cyano, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxyethyl, cyanomethyl,aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, azetidinyl,piperidyl, piperazinyl, methoxy, methylamino, dimethylamino,cyclopropylamino, cyclopropylmethylamino, 4-ethylpiperazinyl,ethoxycarbonylethyl, 4-carboxypiperidyl, cyclobutylamino,3-carboxypyrrolidinyl, and carboxymethylamino; or pyridin-2(1H)-ketosubstituted with any one or more of deuterium, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxyethyl, cyanomethyl,aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, piperidyl,piperazinyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, andethoxycarbonylpropyl;

R³ is any one of hydrogen, deuterium, fluorine, chlorine, and bromine;

R⁴ is hydrogen or deuterium;

R⁵ is any one of hydrogen, deuterium, methyl, ethyl, isopropyl, butyl,sec-butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl, and cyclopropyl.

A compound as the sixth embodiment of formula I, wherein:

Ar is phenyl substituted with any one or more of deuterium, halogen,hydroxy, cyano, C₁₋₆ alkyl, a substituted C₁₋₆ alkyl, C₁₋₆ alkoxy, andC₁₋₆ alkylamino, wherein the substituted C₁₋₆ alkyl is substituted withany one or more of fluorine, hydroxy, cyano, aryl, heteroaryl, amino,C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkyl, carboxyl, and C₃₋₇heterocycloalkyl.

A compound as the seventh embodiment of formula I, wherein:

Ar is phenyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, cyano, methyl, ethyl, trifluoromethyl,trifluoromethylmethyl, hydroxymethyl, cyanomethyl, benzyl,pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,morpholinylethyl, methoxy, and methylamino.

A compound as the eighth embodiment of formula I, wherein:

Ar is pyrazolyl substituted with any one or more of deuterium, halogen,hydroxy, cyano, C₁₋₆ alkyl, a substituted C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkylamino, C₃₋₇ heterocycloalkyl, and —C₁₋₆ alkyl-C(═O)—R⁶, wherein thesubstituted C₁₋₆ alkyl is substituted with any one or more of fluorine,hydroxy, cyano, aryl, heteroaryl, amino, C₁₋₆ alkoxy, C₁₋₆ alkylamino,C₃₋₇ cycloalkyl, carboxyl, and C₃₋₇ heterocycloalkyl; wherein R⁶ is anyone of hydroxy, amino, carboxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkylamino,C₃₋₇ heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl.

A compound as the ninth embodiment of formula I, wherein:

Ar is pyrazolyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, cyano, methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl,trifluoromethylmethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl,cyanomethyl, benzyl, pyrazolylmethyl, aminomethyl, methoxymethyl,methoxyethyl, methoxypropyl, methylaminoethyl, cyclopropylmethyl,carboxymethyl, carboxyethyl, carboxypropyl, morpholinylethyl, methoxy,methylamino, oxetanyl, piperidyl, and ethoxycarbonylethyl.

A compound as the tenth embodiment of formula I, wherein:

Ar is pyridinyl substituted with any one or more of deuterium, halogen,hydroxy, amino, cyano, C₁₋₆ alkyl, a substituted C₁₋₆ alkyl, and C₃₋₇heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy C₁₋₆ alkoxy, C₁₋₆ alkylamino,di-C₁₋₆ alkylamino, C₃₋₇ cycloalkylamino, C₃₋₇ cycloalkyl C₁₋₆alkylamino, carboxyl C₁₋₆ alkylamino, —C₃₋₇ heterocycloalkyl-R⁶, —C₁₋₆alkyl-C(═O)—R⁶, and —N(R⁷)—C(═O)—R⁸, wherein the substituted C₁₋₆ alkylis substituted with any one or more of fluorine, C₁₋₆ alkoxy, C₁₋₆alkylamino, and C₃₋₇ heterocycloalkyl; wherein R⁶ is any one of hydroxy,amino, carboxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl,C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkylamino, C₃₋₇heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl;

R⁷ is any one of hydrogen, deuterium, C₁₋₆ alkyl, and C₃₋₇ cycloalkyl;

R⁸ is any one of hydrogen, deuterium, C₁₋₆ alkyl, aryl, heteroaryl, C₃₋₇cycloalkyl, aryl C₁₋₆ alkyl, heteroaryl C₁₋₆ alkyl, and C₃₋₇heterocycloalkyl.

A compound as the eleventh embodiment of formula I, wherein:

Ar is pyridinyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, amino, cyano, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, trifluoromethyl,trifluoromethylmethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, morpholinylethyl, morpholinyl, piperidyl, piperazinyl,pyrrolidinyl, azetidinyl, methoxy, methoxyethoxy, methylamino,dimethylamino, cyclopropylamino, cyclobutylamino,cyclopropylmethylamino, 4-hydroxypiperidyl, 4-methylpiperazinyl,4-ethylpiperazinyl, 4-acetylpiperazinyl, ethoxycarbonylethyl,acetylamino, and carboxymethylamino.

A compound as the twelfth embodiment of formula I, wherein:

Ar is 1, 2, 4-triazolyl substituted with any one or more of deuterium,halogen, hydroxy, amino, C₁₋₆ alkyl, and C₁₋₆ alkyl substituted with anyone or more of fluorine, hydroxy, amino, C₁₋₆ alkoxy, C₁₋₆ alkylamino,C₃₋₇ cycloalkyl, carboxyl, and C₃₋₇ heterocycloalkyl.

A compound as the thirteenth embodiment of formula I, wherein:

Ar is 1, 2, 4-triazolyl substituted with any one or more of deuterium,fluorine, chlorine, bromine, hydroxy, amino, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxymethyl, hydroxyethyl,hydroxypropyl, aminomethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl, andmorpholinylethyl.

A compound as the fourteenth embodiment of formula I, wherein:

Ar is thiazolyl substituted with any one or more of deuterium, halogen,hydroxy, amino, C₁₋₆ alkyl, a substituted C₁₋₆ alkyl, C₃₋₇heterocycloalkyl, —C₃₋₇ heterocycloalkyl-R⁶, and —C₁₋₆ alkyl-C(═O)—R⁶,wherein the substituted C₁₋₆ alkyl is substituted with any one or moreof fluorine, hydroxy, cyano, amino, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇cycloalkyl, carboxyl, and C₃₋₇ heterocycloalkyl; wherein R⁶ is any oneof hydroxy, amino, carboxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkylamino,C₃₋₇ heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl.

A compound as the fifteenth embodiment of formula I, wherein:

Ar is thiazolyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, amino, methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl,trifluoromethylmethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl,cyanomethyl, aminomethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, oxetanyl, piperidyl, morpholinyl,piperazinyl, 4-hydroxypiperidyl, 4-methylpiperazinyl, andethoxycarbonylethyl.

A compound as the sixteenth embodiment of formula I, wherein:

Ar is pyrimidyl substituted with any one or more of deuterium, halogen,hydroxy, amino, cyano, C₁₋₆ alkyl, a substituted C₁₋₆ alkyl, C₃₋₇heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₃₋₇cycloalkylamino, C₃₋₇ cycloalkyl C₁₋₆ alkylamino, carboxyl C₁₋₆alkylamino, —C₃₋₇ heterocycloalkyl-R⁶, and —C₁₋₆ alkyl-C(═O)—R⁶, whereinthe substituted C₁₋₆ alkyl is substituted with any one or more offluorine, hydroxy, cyano, amino, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇cycloalkyl, carboxyl, and C₃₋₇ heterocycloalkyl; wherein R⁶ is any oneof hydroxy, amino, carboxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkylamino,C₃₋₇ heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl.

A compound as the seventeenth embodiment of formula I, wherein:

Ar is pyrimidyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, amino, cyano, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxyethyl, cyanomethyl,aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, azetidinyl,piperidyl, piperazinyl, methoxy, methylamino, dimethylamino,cyclopropylamino, cyclopropylmethylamino, 4-ethylpiperazinyl,ethoxycarbonylethyl, 4-carboxypiperidyl, cyclobutylamino,3-carboxypyrrolidinyl, and carboxymethylamino.

A compound as the eighteenth embodiment of formula I, wherein:

Ar is pyridin-2(1H)-keto substituted with any one or more of deuterium,C₁₋₆ alkyl, a substituted C₁₋₆ alkyl, C₃₋₇ heterocycloalkyl, and —C₁₋₆alkyl-C(═O)—R⁶, wherein the substituted C₁₋₆ alkyl is substituted withany one or more of fluorine, hydroxy, cyano, amino, C₁₋₆ alkoxy, C₁₋₆alkylamino, C₃₋₇ cycloalkyl, carboxyl, and C₃₋₇ heterocycloalkyl;wherein R⁶ is any one of hydroxy, amino, carboxyl, C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇cycloalkylamino, C₃₋₇ heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl.

A compound as the nineteenth embodiment of formula I, wherein:

Ar is pyridin-2(1H)-keto substituted with any one or more of deuterium,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxyethyl, cyanomethyl, aminoethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, carboxypropyl, morpholinylethyl, morpholinyl,pyrrolidinyl, piperidyl, piperazinyl, ethoxycarbonylmethyl,ethoxycarbonylethyl, and ethoxycarbonylpropyl.

A typical approach to synthesize the compound of formula I is describedbelow to further describe the technical solution of this invention,specific examples of which is shown below:

Compound 1 is condensed with TsNHNH₂ to give product 2;

Product 2 is treated with aldehyde 3 in the presence of EtONa to giveproduct 4;

Product 4 is treated with ammonium acetate to give product 5 byreductive amination;

Product 5 is acylated with formic acid to give amide 6;

Amide 6 is treated with oxalyl chloride in the presence of FeCl₃ to givecrude product, which is further treated with concentrated sulfuric acidin methanol to give product 7;

Compound 7 is treated with ethyl 2-acetyl-3-ethoxyacrylate 8 to giveproduct 9 by ring-closing reaction;

Product 9 is oxidated to product 10 by chloranil;

Product 10 was treated with aryl or heteroaryl boronic acid to giveproduct 11 by Suzuki coupling;

Product 11 is hydrolyzed by sodium hydroxide or lithium hydroxide togive product 12.

As a variation of the above typical approach, another reaction route isshown below. Wherein the reaction route of compound 1 to product 11 isunchanged, and only the partial reaction route which changes after theproduct 11 is shown below. Wherein Y refers to heteroaryl, Z refers toC₁₋₆ alkyl, or C₁₋₆ alkyl which is substituted with any one of fluorine,hydroxyl, cyano, aryl, heteroaryl, amino, C₁₋₆ alkoxy, C₁₋₆ alkylamino,C₃₋₇ cycloalkyl, carboxyl and heterocycloalkyl; X refers to halogen.

Further, when Y is heteroaryl, a substituent can be added by a modifiedapproach into Y group. Product 11 is first treated with halide Z—X underbasic conditions to give the product 13 by substitution reaction.Thereafter, product 13 is hydrolyzed by sodium hydroxide or lithiumhydroxide to give product 14.

Further, when Ar is 1H-1,2,4-triazol-3-yl, it can also be obtained by amodified approach. Product 10 is first substituted with cuprous cyanideto give the product 15. Thereafter, product 15 is hydrolyzed byconcentrated sulfuric acid to give product 16, which is then treatedwith hydrazine hydrate and DMF-DMAc to give product 17.

EXAMPLES

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention.

Abbreviations used herein are as follows:

AcOH: acetic acid

CDCl3: deuterated chloroform

Dioxane: 1,4-dioxane

CC₅₀: 50% cytotoxic concentration

CO₂: carbon dioxide

Con. H₂SO₄: concentrated sulfuric acid

CuCN: Copper(I) cyanide

DCM: dichloromethane

DMAc: N,N-dimethylacetamide

DME: dimethoxyethane

DMF: N,N-dimethylformamide

DMSO: dimethylsufoxide

DMSO-d₆: dimethylsulfoxide-d₆

EtOH: ethanol

EtONa: sodium ethoxide

FeCl₃: iron (III) chloride

g: gram

HCOOH: formic acid

Hz: Hertz

h: hour

IC₅₀: half maximal inhibition concentration

LiOH: lithium hydroxide

MeOH: methanol

mg: milligram

mL: milliliter

mmol: millimolar

MHz: mega Hertz

NaBH₃CN: sodium cyanoborohydride

NaOH: sodium hydroxide

N₂H₄.H₂O: hydrazine hydrate

NH₄OAc: ammonium acetate

NMP: N-methyl-2-pyrolidone

NMR: nuclear magnetic resonance

M: molar/liter

PBS: phosphate buffered saline

Pd: Palladium

PdCl2(dppf): [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

TCQ: tetrachloro-p-benzoquinone

TLC: thin layer chromatography

TsNHNH₂: p-toluenesulfonhydrazide

μM: micromolar/liter

g: microgram

μL: microliter

δ: chemical shift

General Experimental Conditions

Generally, the reactions described in the examples were performed undernitrogen atmosphere.

The intermediates and final compounds were purified by columnchromatography, preparative TLC and ICSO flash chromatographyinstrument.

LC-MS spectrometer is equipped with QDa detector and ESI ionizationsource from Waters ACQUITY Arc, and the molecular ion [M⁺] peak isnormally reported as [M+H]⁺.

Injection volume is defined by sample concentrate, flow rate is 1.2mL/min, and the peaks in chromatogram are recorded in the UV wavelengthat 220 and 254 nm. Mobile phase A is 0.01% aqueous formic acid solution,and mobile phase B is 0.01% formic acid in CH₃CN. The gradient eluentconditions are shown as in Table 1 and Table 2.

TABLE 1 gradient eluent 1 time (min) A(H₂O, 0.01% HCOOH) B(CH₃CN, 0.01%HCOOH) 0.0-0.3 95-85  5-15 0.3-3.2 85-20 15-80 3.2-3.8 20-5  80-95 3.8-3.81  5-95 95-5  3.81-4.0  95 5

TABLE 2 gradient eluent 2 time (min) A(H₂O, 0.01% HCOOH) B(CH₃CN, 0.01%HCOOH) 0.00-5.90 95-5 5-95 5.90-5.91  5-95 95-5  5.91-6.00 95 5

NMR spectrums are recorded by Varian 400 MHz NMR spectrometer, CDCl₃ andDMSO-d₆ are often used as solvents, chemical shift is reported as ppm,and the peaks in the spectrum are described as follows: s (single peak),d (double peak), t (triple peak), q (quadruple peak), m (multiple peak),dd (double-double peak), and coupling constants are indicated as Hz.

Preparative Examples Example 16-isopropyl-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 1a: Preparation ofN′-(3-bromo-4-methoxybenzylidene)-4-methylbenzenesulfonohydrazide

To a solution of 3-bromo-4-methoxybenzaldehyde (20 g, 93 mmol) inmethanol (300 mL) was added p-toluenesulfonyl hydrazide (20.8 g, 111.6mmol), and the reaction mixture was allowed to stir at RT (20° C.) for16 h. A white solid was precipitated, then evaporation of half a volumeof MeOH (150 mL), and collected by filtration. The resulted white solidwas dried in vacuum asN′-(3-bromo-4-methoxybenzylidene)-4-methylbenzenesulfono hydrazide (34.5g), which was used for next stage without further purification.

Step 1b: Preparation of 1-(3-bromo-4-methoxyphenyl)-3-methylbutan-2-one

To a solution ofN′-(3-bromo-4-methoxybenzylidene)-4-methylbenzenesulfonohydrazide (7.251g, 45 mmol) in ethanol (400 mL) was added NaOEt (3.06 g, 45 mmol), andthe reaction mixture was allowed to stir at RT for 15 min, followed byadding isobutyraldehyde (2.16 g, 30 mmol). Then, the mixture was heatedat 60° C. for 1 day. Ethanol was evaporated under reduced pressure, andthe resulted residue was partitioned between ethyl acetate (200 mL) andwater (100 mL), allowed to stir for 10 min. The organic phase wascollected, and the water phase was extracted with EtOAc four times (50mL×4), the combined organic phase was washed with brine (100 mL×3),dried over anhydrous sodium sulfate. The drying agent was filtered off,and the filtrate was concentrated under reduced pressure to provide thecrude product. The crude product was purified by flash columnchromatography to provide1-(3-bromo-4-methoxyphenyl)-3-methylbutan-2-one as colorless oil (4.1g).

Step 1c: Preparation of1-(3-bromo-4-methoxyphenyl)-3-methylbutan-2-amine

To a solution of 1-(3-bromo-4-methoxyphenyl)-3-methylbutan-2-one (4.1 g,15.1 mmol) in MeOH (60 mL) was added ammonium acetate (17.46 g, 226.5mmol) and NaBH₃CN (1.9 g, 30.2 mmol), and the reaction mixture wasallowed to stir at RT for 2 days. TLC showed that the starting materialwas completely consumed. The reaction was quenched with water, followedby adding 2.0 M aqueous NaOH (20 mL), then, the mixture was allowed tostir for 1 h. The reaction mixture was extracted with EtOAc, and theorganic phase was washed with water (50 mL×3) and brine, dried overanhydrous sodium sulfate, filtered, and concentrated to provide1-(3-bromo-4-methoxyphenyl)-3-methylbutan-2-amine as colorless oil,which was used for next stage without further purification.

Step 1d: Preparation ofN-(1-(3-bromo-4-methoxyphenyl)-3-methylbutan-2-yl)formamide

To a solution of 1-(3-bromo-4-methoxyphenyl)-3-methyl-2-butylamine (6.2g, 22.8 mmol) in dioxane (60 mL) was added formic acid (3.1 g, 68.4mmol), and the reaction mixture was heated at reflux for 16 h. TLCshowed that the starting material was completely consumed. The volatileswere evaporated under reduced pressure, and the resulted residue wasstirred in EtOAc (50 mL) and 1 M NaOH aqueous solution (20 mL) for 20minutes. The organic phase was collected, and the water phase wasextracted with EtOAc (30 mL×2). The combined organic phase was washedwith brine (50 mL×3), dried over anhydrous sodium sulfate, filtered, andconcentrated. The resulted crude product was purified by flash columnchromatography to provideN-(1-(3-bromo-4-methoxyphenyl)-3-methylbutan-2-yl)formamide as colorlessoil (4.1 g).

Step 1e: Preparation of6-bromo-3-isopropyl-7-methoxy-3,4-dihydroisoquinoline

To a solution of N-(1-(3-bromo-4-methoxyphenyl)-3-methylbutan-2-yl)formamide (150 mg, 0.5 mmol) in DCM (10 mL) was added oxalyl chloride(53 μL, 0.63 mmol) under nitrogen, and the reaction mixture was allowedto stir at RT for 1 h, then cooled to −10° C., followed by adding FeCl₃(121.7 mg, 0.75 mmol). The reaction mixture was allowed to slowly riseto RT, and continue stirring for 20 h. Then, 2 M HCl (10 mL) was addedto quench the reaction and the mixture was stirred for additional 1 h.The organic phase was washed with water and brine, dried over anhydroussodium sulfate, filtered and concentrated. The resulted oily residue wasdissolved in MeOH (10 mL) and con. Sulfuric acid (0.5 mL), and allowedto heat at reflux for 4 h. The reaction mixture was cooled to RT and thevolatiles were evaporated under reduced pressure, and the residue wasdissolved in EtOAc (20 mL), basified till pH=11 with saturated aqueoussodium carbonate solution, and the water phase was extracted with EtOAc(15 mL×3). The combined organic phase was dried over anhydrous sodiumsulfate, filtered and concentrated, providing6-bromo-3-isopropyl-7-methoxy-3,4-dihydroisoquinoline as a yellow oil(130 mg, 92.1% yield), which was used for next stage without furtherpurification.

Step 1f: Preparation of ethyl 9-bromo-6-isopropyl-10-methoxy-2-oxo-1,6,7,11b-tetrahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

To a solution of 6-bromo-3-isopropyl-7-methoxy-3,4-dihydroisoquinoline(130 mg, 0.46 mmol) in EtOH (10 mL) was added ethyl2-(ethoxylmethylene)-3-oxo-butyrate (514 mg, 2.76 mmol) under nitrogenatmosphere, and the reaction mixture was heated at reflux for 20 h, thenconcentrated under reduced pressure to provide crude product ethyl9-bromo-6-isopropyl-10-methoxy-2-oxo-1,6,7,11b-tetrahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylateas a brown oil (200 mg), which was used for next stage without furtherpurification.

Step 1g: Preparation of ethyl9-bromo-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

To a solution of ethyl9-bromo-6-isopropyl-10-methoxy-2-oxo-1,6,7,11b-tetrahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(200 mg) in DME (5 mL) was added TCQ (113.1 mg, 0.46 mmol), and thereaction mixture was heated at reflux for 2 h. Then, the volatiles wereevaporated and the resulted residue was partitioned between EtOAc (20mL) and water (30 mL), the organic phase was collected and washed withbrine (20 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated to provide a crude product, then purified by preparativeTLC to give ethyl9-bromo-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate as brown solid (78 mg).

Step 1h: Preparation of ethyl6-isopropyl-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

To a solution of ethyl9-bromo-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(78 mg, 0.186 mmol) in dioxane (2 mL) and water (0.5 mL) was added(1H-pyrazol-4-yl)boronic acid (31.2 mg, 0.279 mmol), potassium carbonate(77.1 mg, 0.558 mmol) and PdCl₂(dppf) (14 mg, 0.019 mmol) undernitrogen, and the reaction mixture was allowed to heat at 85° C. andstirred for 20 h. The reaction mixture was partitioned between EtOAc (20mL) and water (30 mL), and the organic phase was washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated, and theresulted residue was purified by preparative TLC to provide ethyl6-isopropyl-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquino-line-3-carboxylateas a white solid (20 mg).

Step 1i: Preparation of6-isopropyl-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

To a solution of ethyl6-isopropyl-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(20 mg, 0.049 mmol) in EtOH (2 mL) was added 10% NaOH solution (0.4 mL),and the reaction mixture was allowed to stir at RT for 4 h. Then, thevolatiles were evaporated in vacuum, and the residue was partitionedbetween water (20 mL) and EtOAc (20 mL), the water phase was extractedwith EtOAc (20 mL×4), and water phase was acidified till pH=2. Then, thewater phase was extracted with EtOAc (10 mL×5), and the combined organicphase was washed with water (20 mL×5), then concentrated to afford6-isopropyl-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (13 mg) as white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 13.06 (s, 1H),8.82 (s, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 7.75 (s, 1H), 7.61 (s, 1H),7.59 (s, 1H), 4.50-4.46 (m, 1H), 4.01 (s, 3H), 3.32-3.29 (m., 1H),3.19-3.15 (m, 1H), 1.65-1.61 (m, 1H), 0.89 (d, J=6.4 Hz, 3H), 0.71 (d,J=6.8 Hz, 3H). MS observed (ESI⁺) [(M+H)⁺]: 380.

Example 26-isopropyl-10-methoxy-2-oxo-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 2a: Preparation of ethyl6-isopropyl-10-methoxy-2-oxo-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

To a solution of ethyl6-isopropyl-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.123 mmol) in DMF (1 mL) was added 1,1,1-trifluoro-2-iodoethane(103 mg, 0.491 mmol) and potassium carbonate (67.8 mg, 0.491 mmol), andthe reaction mixture was heated at 75° C. and stirred for 4 h. TLCshowed that the starting material was completely consumed, and thereaction mixture was partitioned between DCM and water, the water phasewas extracted with DCM (10 mL×3), the combined organic phase was washedwith brine (10 mL×3), dried over anhydrous sodium sulfate, filtered andconcentrated. The resulted residue was purified by preparative TLC toprovide ethyl6-isopropyl-10-methoxy-2-oxo-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylateas a light yellow solid (21 mg).

Step 2b: Preparation of6-isopropyl-10-methoxy-2-oxo-9-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

To a solution of ethyl6-isopropyl-10-methoxy-2-oxo-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(21 mg, 0.043 mmol) in EtOH (1 mL) was added 10% NaOH solution (0.5 mL),and the reaction mixture was allowed to stir at RT for 2 h. TLC showedthat the starting material was completely consumed, and the volatileswere evaporated in vacuum. The resulted residue was dissolved in water(20 mL), extracted with DCM (5 mL×2), and the water phase was acidifiedtill pH=2, then extracted with DCM (10 mL×2), and the combined organicphase was washed with water (20 mL×5), concentrated to provide6-isopropyl-10-methoxy-2-oxo-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (12 mg) as light brown solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.23 (s,1H), 8.40 (s, 1H), 8.18 (s, 1H), 7.79 (s, 1H), 7.64 (s, 1H), 7.61 (s,1H), 5.21 (q, J=9.2 Hz, 2H), 4.53-4.45 (m, 1H), 4.03 (s, 3H), 3.30-3.14(m, 2H), 1.68-1.55 (m, 1H), 0.88 (d, J=6.4 Hz, 3H), 0.71 (d, J=6.4 Hz,3H). MS observed (ESI⁺) [(M+H)⁺]: 462.

Example 36-isopropyl-10-methoxy-9-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 3a: Preparation of ethyl6-isopropyl-10-methoxy-9-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-isopropyl-10-methoxy-9-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(36 mg) was prepared as yellowish oil by using ethyl6-isopropyl-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.123 mmol) and 1-bromo-2-methoxyethane (69.2 mg, 0.491 mmol)according to method in example 2, step 2a.

Step 3b: Preparation of6-isopropyl-10-methoxy-9-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-isopropyl-10-methoxy-9-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (9 mg) was prepared as yellow solid by using ethyl6-isopropyl-10-methoxy-9-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(36 mg, 0.08 mmol) according to method in example 2, step 2b. ¹H NMR(400 MHz, DMSO-d₆): δ 8.82 (s, 1H), 8.25 (s, 1H), 8.03 (s, 1H), 7.73 (s,1H), 7.61 (s, 1H), 7.59 (s, 1H), 4.52-4.40 (m, 1H), 4.31 (t, J=5.2 Hz,2H), 4.01 (s, 3H), 3.71 (t, J=5.2 Hz, 2H), 3.32-3.29 (m, 1H), 3.24 (s,3H), 3.22-3.10 (m, 1H), 1.68-1.54 (m, 1H), 0.88 (d, J=6.4 Hz, 3H), 0.71(d, J=6.4 Hz, 3H). MS observed (ESI⁺) [(M+H)⁺]: 438.

Example 49-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 4a: Preparation of ethyl9-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl9-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(40 mg) was prepared as yellow oil by using ethyl6-isopropyl-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.123 mmol) and 3-bromo-1-propanol (68 mg, 0.491 mmol) accordingto method in example 2, step 2a.

Steps 4b: Preparation of9-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

9-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (11.1 mg) was prepared as white solid by using ethyl9-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylateaccording to method in example 2, step 2b. ¹H NMR (400 MHz, DMSO-d₆): δ8.82 (s, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.73 (s, 1H), 7.61 (s, 1H),7.58 (s, 1H), 4.50-4.45 (m, 1H), 4.20 (t, J=6.4 Hz, 2H), 4.01 (s, 3H),3.40 (t, J=6.4 Hz, 2H), 3.22-3.19 (m, 1H), 3.18-3.14 (m, 1H), 1.99-1.89(m, 2H), 1.69-1.55 (m, 1H), 0.88 (d, J=6.4 Hz, 3H), 0.71 (d, J=6.4 Hz,3H). MS observed (ESI⁺) [(M+H)⁺]: 438.

Example 59-(1-isobutyl-1H-pyrazol-4-yl)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 5a: Preparation of ethyl9-(1-isobutyl-1H-pyrazolo-4-yl)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl9-(1-isobutyl-1H-pyrazolo-4-yl)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(12 mg) as white solid was prepared by using ethyl6-isopropyl-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.123 mmol) and 1-bromo-2-methylpropane (168 mg, 1.23 mmol)according to method in example 2, step 2a.

Step 5b: Preparation of9-(1-isobutyl-1H-pyrazol-4-yl)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

9-(1-isobutyl-1H-pyrazol-4-yl)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid as light yellow solid (9 mg) was prepared by using ethyl9-(1-isobutyl-1H-pyrazol-4-yl)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(12 mg, 0.03 mmol) according to method in example 2, step 2b. ¹H NMR(400 MHz, DMSO-d₆): δ 16.67 (s, 1H), 8.82 (s, 1H), 8.25 (s, 1H), 8.03(s, 1H), 7.73 (s, 1H), 7.61 (s, 1H), 7.59 (s, 1H), 4.51-4.45 (m, 1H),4.01 (s, 3H), 3.96 (d, J=7.2 Hz, 2H), 3.33-3.30 (m, 1H), 3.19-3.15 (m,1H), 2.16-2.13 (m, 1H), 1.68-1.63 (m, 1H), 0.89-0.85 (m, 9H), 0.71 (d,J=6.8 Hz, 3H). MS observed (ESI⁺) [(M+H)⁺]: 436.

Example 66-isopropyl-10-methoxy-2-oxo-9-(1-propyl-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 6a: Preparation of ethyl6-isopropyl-10-methoxyl-2-oxo-9-(1-propyl-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-isopropyl-10-methoxyl-2-oxo-9-(1-propyl-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(32 mg) as white solid was prepared by using ethyl6-isopropyl-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.123 mmol) and 1-bromopropane (151 mg, 1.23 mmol) according tomethod in example 2, step 2a.

Step 6b: Preparation of6-isopropyl-10-methoxy-2-oxo-9-(1-propyl-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-isopropyl-10-methoxy-2-oxo-9-(1-propyl-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (20 mg) as yellow solid was prepared by using ethyl6-isopropyl-10-methoxy-2-oxo-9-(1-propyl-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylateaccording to method in example 2, step 2b. ¹H NMR (400 MHz, DMSO-d₆): δ8.69 (s, 1H), 8.25 (s, 1H), 8.01 (s, 1H), 7.71 (s, 1H), 7.56 (s, 1H),7.43 (s, 1H), 4.42-4.35 (m, 1H), 4.10 (t, J=6.8 Hz, 2H), 4.00 (s, 3H),3.19-3.10 (m, 2H), 1.86-1.79 (m, 2H), 1.68-1.62 (m, 1H), 0.89-0.83 (m,6H), 0.71 (d, J=6.4 Hz, 3H). MS observed (ESI⁺) [(M+H)⁺]: 422.

Example 76-isopropyl-10-methoxy-9-(6-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 7a: Preparation of ethyl6-isopropyl-10-methoxy-9-(6-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-isopropyl-10-methoxy-9-(6-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(61 mg) as yellow solid was prepared by using ethyl9-bromo-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.238 mmol) and (6-methylpyridin-3-yl)boronic acid (42.3 mg,0.309 mmol) according to method in example 1, step 1h.

Step 7b: Preparation of6-isopropyl-10-methoxy-9-(6-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-isopropyl-10-methoxy-9-(6-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (21 mg) as light yellow solid was prepared by using ethyl6-isopropyl-10-methoxy-9-(6-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido-[2,1-a]isoquinoline-3-carboxylate(61 mg, 0.14 mmol) according to method in example 1, step 1i. ¹H NMR(400 MHz, DMSO-d₆): δ 8.87 (s, 1H), 8.83 (s, 1H), 7.75-7.71 (m, 4H),7.59 (m, 1H), 4.54-4.51 (m, 1H), 3.95 (s, 3H), 3.26-3.22 (m, 2H), 2.68(s, 3H), 1.26-1.23 (m, 1H), 0.89 (d, J=4.0 Hz, 3H), 0.73 (d, J=4.0 Hz,3H). MS observed (ESI⁺) [(M+H)⁺]: 405

Example 86-(tert-butyl)-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 8a: Preparation of1-(3-bromo-4-methoxyphenyl)-3,3-dimethylbutan-2-one

1-(3-bromo-4-methoxyphenyl)-3,3-dimethylbutan-2-one (1.82 g) ascolorless oil was prepared by usingN′-(3-bromo-4-methoxybenzylidene)-4-methylbenzene sulfonylhydrazide(8.62 g, 22.5 mmol) and pivaldehyde (1.29 g, 15 mmol) according tomethod in example 1, step 1b.

Step 8b: Preparation of1-(3-bromo-4-methoxyphenyl)-3,3-dimethylbutan-2-amine

1-(3-bromo-4-methoxyphenyl)-3,3-dimethylbutan-2-amine as colorless oil(2.1 g) was prepared by using1-(3-bromo-4-methoxyphenyl)-3,3-dimethylbutan-2-one (1.82 g, 6.38 mmol)and ammonium acetate (7.38 g, 95.7 mmol) according to method in example1, step 1c.

Step 8c: Preparation ofN-(1-(3-bromo-4-methoxyphenyl)-3,3-dimethylbutan-2-yl)formamide

N-(1-(3-bromo-4-methoxyphenyl)-3,3-dimethylbutan-2-yl)formamide asoff-white solid (1.82 g) was prepared by using1-(3-bromo-4-methoxyphenyl)-3,3-dimethylbutan-2-amine (2.1 g) and formicacid (2 mL) according to method in example 1, step 1d.

Step 8d: Preparation of6-bromo-3-(tert-butyl)-7-methoxy-3,4-dihydroisoquinoline

6-bromo-3-(tert-butyl)-7-methoxy-3,4-dihydroisoquinoline (1.62 g) asyellow oil was prepared by usingN-(1-(3-bromo-4-methoxyphenyl)-3,3-dimethylbutan-2-yl) formamide (1.82g, 5.8 mmol) according to method in example 1, step 1e.

Step 8e: Preparation of ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-1,6,7,11b-tetrahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-1,6,7,11b-tetrahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylateas brown oil (3.2 g) was prepared by using6-bromo-3-(tert-butyl)-7-methoxy-3,4-dihydroisoquinoline (1.62 g, 5.5mmol) and ethyl 2-(ethoxymethylene)-3-oxo-butyrate (4.1 g, 22 mmol)according to method in example 1, step 1f.

Step 8f: Preparation of ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylateas brown solid (920 mg) was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-1,6,7,11b-tetrahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(3.2 g) and TCQ (1.35 g, 5.5 mmol) according to method in example 1,step 1g.

Step 8g: Preparation of ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylateas brown solid (150 mg) was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(600 mg, 1.38 mmol) and (1H-pyrazol-4-yl)boronic acid (463 mg, 4.14mmol) according to method in example 1, step 1h.

Step 8h: Preparation of6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (3 mg) as light yellowish solid was prepared by using ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.119) according to method in example 1, step 1i. ¹H NMR (400MHz, DMSO-d₆): δ 8.76 (s, 1H), 8.16 (s, 2H), 7.74 (s, 1H), 7.58 (s, 1H),7.57 (s, 1H), 4.63-4.58 (m, 1H), 4.00 (s, 3H), 3.45-3.38 (m, 1H),3.28-3.24 (m, 1H), 0.74 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 394.

Example 96-(tert-butyl)-9-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 9a: Preparation of ethyl6-(tert-butyl)-9-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(40 mg) as yellow solid was prepared by using ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(80 mg, 0.19 mmol) and 3-bromopropanol (264 mg, 1.9 mmol) according tomethod in example 2, step 2a.

Step 9b: Preparation of6-(tert-butyl)-9-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (20.7 mg) as white solid was prepared by using ethyl6-(tert-butyl)-9-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(40 mg, 0.09 mmol) according to method in example 2, step 2b. ¹H NMR(400 MHz, DMSO-d₆): δ 16.61 (s, 1H), 8.75 (s, 1H), 8.25 (s, 1H), 8.01(s, 1H), 7.72 (s, 1H), 7.58 (s, 1H), 7.57 (s, 1H), 4.61-4.59 (m, 2H),4.20 (t, J=6.8 Hz, 2H), 4.00 (s, 3H), 3.43-3.38 (m, 4H), 1.95 (dd,J=12.8, 6.4 Hz, 2H), 0.74 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 452.

Example 106-(tert-butyl)-10-methoxy-2-oxo-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 10a: Preparation of ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(10 mg) as yellow solid was prepared by using ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.12 mmol) and 2-bromo-1,1,1-trifluoroethane (193 mg, 1.2 mmol)according to method in example 2, step 2a.

Step 10b: Preparation of6-(tert-butyl)-10-methoxy-2-oxo-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-2-oxo-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (5.8 mg) as grey solid was prepared by using ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(10 mg, 0.02 mmol) according to method in example 2, step 2b. ¹H NMR(400 MHz, DMSO-d₆): δ 8.76 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 7.77 (s,1H), 7.61 (s, 1H), 7.60 (s, 1H), 5.20 (q, J=9.2 Hz, 2H), 4.61 (d, J=6.0Hz, 1H), 4.01 (s, 3H), 3.45-3.38 (m, 2H), 0.74 (s, 9H). MS observed(ESI⁺) [(M+H)⁺]: 476.

Example 116-(tert-butyl)-10-methoxy-9-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-2-carboxylicAcid

Step 11a: Preparation of ethyl6-(tert-butyl)-10-methoxy-9-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-10-methoxy-9-(1-(oxetan-3-yl)-1H-pyrazol-4-yl]-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(10 mg) as yellow solid was prepared by using ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.12 mmol) and 3-bromooxetane (179 mg, 1.2 mmol) according tomethod in example 2, step 2a.

Step 11b: Preparation of6-(tert-butyl)-10-methoxy-9-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-9-(1-(oxetan-3-yl)-1H-pyrazol-4-yl]-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (6.7 mg) as yellow solid was prepared by using ethyl6-(tert-butyl)-10-methoxy-9-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(10 mg, 0.03 mmol) according to method in example 2, step 2b. ¹H NMR(400 MHz, DMSO-d₆): δ 8.76 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 7.76 (s,1H), 7.59 (s, 1H), 7.58 (s, 1H), 4.95-4.93 (m, 4H), 4.61 (d, J=6.4 Hz,1H), 4.04 (s, 4H), 3.45-3.38 (m, 2H), 0.74 (s, 9H). MS observed (ESI⁺)[(M+H)⁺]: 450.

Example 126-(tert-butyl)-9-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 12a: Preparation of ethyl6-(tert-butyl)-9-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(29 mg) as white solid was prepared by using ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.12 mmol) and 1-bromo-2-propanol (165 mg, 1.2 mmol) accordingto method in example 2, step 2a.

Step 12b: Preparation of6-(tert-butyl)-9-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (13.4 mg) as white solid was prepared by using ethyl6-(tert-butyl)-9-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(29 mg, 0.06 mmol) according to method in example 2, step 2b. ¹H NMR(400 MHz, DMSO-d₆): δ 8.75 (s, 1H), 8.22 (s, 1H), 8.02 (s, 1H), 7.73 (s,1H), 7.58 (s, 1H), 7.57 (s, 1H), 4.93 (t, J=4.4 Hz, 1H), 4.61 (d, J=5.6Hz, 1H), 4.04 (s, 2H), 4.00 (s, 3H), 3.42-3.39 (m, 2H), 1.09-1.02 (m,3H), 0.74 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 452.

Example 136-(tert-butyl)-10-methoxy-9-(1-methyl-1H-pyrazol-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 13a: Preparation of ethyl6-(tert-butyl)-10-methoxy-9-(1-methyl-1H-pyrazol-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-10-methoxy-9-(1-methyl-1H-pyrazol-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(64 mg) as yellow solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido-[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (53mg, 0.253 mmol) according to method in example 1, step 1h.

Step 13b: Preparation of6-(tert-butyl)-10-methoxy-9-(1-methyl-1H-pyrazol-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-9-(1-methyl-1H-pyrazol-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (33 mg) as light yellow solid was prepared by using ethyl6-(tert-butyl)-10-methoxy-9-(1-methyl-1H-pyrazol-5-yl)-2-oxo-6,7-dihydro-2H-pyrido-[2,1-a]isoquinoline-3-carboxylate(64 mg, 0.15 mmol) according to method in example 1, step 1i. ¹H NMR(400 MHz, DMSO-d₆): δ 16.48 (s, 1H), 8.79 (s, 1H), 7.70 (s, 1H), 7.69(s, 1H), 7.48-7.47 (m, 1H), 7.39 (s, 1H), 6.34-6.33 (m, 1H), 4.65-4.64(m, 1H), 3.93 (s, 3H), 3.65 (s, 3H), 3.44-3.36 (m, 2H), 0.75 (s, 9H). MSobserved (ESI⁺) [(M+H)⁺]: 408.

Example 146-(tert-butyl)-9-(1-(difluoromethyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 14a: Preparation of ethyl6-(tert-butyl)-9-(1-(difluoromethyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(1-(difluoromethyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(56 mg) as yellow solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(62 mg, 0.253 mmol) according to method in example 1, step 1h.

Step 14b: Preparation of6-(tert-butyl)-9-(1-(difluoromethyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(1-(difluoromethyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (18.4 mg) as light yellow solid was prepared by using ethyl6-(tert-butyl)-9-(1-difluoromethyl-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(56 mg, 0.12 mmol) according to method in example 1, step 1i. ¹H NMR(400 MHz, DMSO-d₆): δ 16.55 (s, 1H), 8.78 (s, 1H), 8.71 (s, 1H), 8.38(s, 1H), 8.02-7.73 (m, 2H), 7.64 (s, 2H), 4.64-4.62 (m, 1H), 4.03 (s,3H), 3.46-3.40 (m, 2H), 0.74 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 444.

Example 156-(tert-butyl)-9-(1,3-dimethyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 15a: Preparation of ethyl6-(tert-butyl)-9-(1,3-dimethyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(1,3-dimethyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(68 mg) as yellow solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido-[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(56 mg, 0.253 mmol) according to method in example 1, step 1h.

Step 15b: Preparation of6-(tert-butyl)-9-(1,3-dimethyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(1,3-dimethyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (7.7 mg) as light yellow solid was prepared by using ethyl6-(tert-butyl)-9-(1,3-dimethyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(68 mg, 0.15 mmol) according to method in example 1, step 1i. ¹H NMR(400 MHz, DMSO-d₆): δ 16.60 (s, 1H), 8.76 (s, 1H), 8.74 (s, 1H), 7.84(s, 1H), 7.60 (s, 1H), 7.56 (s, 1H), 7.34 (s, 1H), 4.61-4.60 (m, 1H),3.91 (s, 3H), 3.80 (s, 3H), 3.42-3.33 (m, 2H), 2.20 (s, 3H), 0.74 (s,9H). MS observed ESI⁺) [(M+H)⁺]: 422.

Example 166-(tert-butyl)-10-methoxy-9-(1-(2-morpholinylethyl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 16a: Preparation of ethyl6-(tert-butyl)-10-methoxy-9-(1-(2-morpholinylethyl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

To a solution of ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.115 mmol) in DMF (1 mL) was added4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine(53 mg, 0.173 mmol), K₂CO₃ (48 mg, 0.345 mmol) and PdCl₂(dppf) (17 mg,0.023) under nitrogen, and the reaction mixture was heated at 95° C. andstirred for 16 h. The reaction mixture was filtered through a celitepad, and the filtrate was diluted with EtOAc, the organic phase waswashed with water (10 mL) and brine (10 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The crudeproduct was purified by flash column chromatography to provide ethyl6-(tert-butyl)-10-methoxy-9-(1-(2-morpholinylethyl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg) as grey-white solid.

Step 16b: Preparation of6-(tert-butyl)-10-methoxy-9-(1-(2-morpholinylethyl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

To a solution of ethyl6-(tert-butyl)-10-methoxy-9-(1-(2-morpholinylethyl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.094 mmol) in MeOH (1 mL) was added 10% NaOH solution (0.2 mL),and the reaction mixture was allowed to stir at RT for 2 h. The volatilewas evaporated and the resulted residue was dissolved in water (5 mL),washed with DCM (10 mL×3). Then the water phase was acidified till pH=2with 1M HCl, extracted with DCM (10 mL×5), and the combined organicphase was washed with water (10 mL×2), dried over anhydrous sodiumsulfate, filtered and concentrated, the crude product was purified bypreparative TLC to provide title compound (21 mg) as yellow solid. ¹HNMR (400 MHz, DMSO-d₆): δ 16.62 (s, 1H), 8.76 (s, 1H), 8.30 (s, 1H),8.01 (s, 1H), 7.72 (s, 1H), 7.58 (s, 1H), 7.57 (s, 1H), 4.60 (d, J=6.0Hz, 1H), 4.28 (t, J=6.2 Hz, 2H), 4.00 (s, 3H), 3.56 (t, J=4.4 Hz, 2H),3.44-3.37 (m, 1H), 3.31-3.24 (m, 2H), 2.74 (t, J=6.4 Hz, 2H), 2.43 (br,3H), 0.74 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 507.

Example 176-(tert-butyl)-10-methoxy-2-oxo-9-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid Hydrochloride

Step 17a: Preparation of ethyl9-(1-(1-tert-butoxycarbonylpiperidin-4-yl)-1H-pyrazol-4-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl9-(1-(1-tert-butoxycarbonylpiperidin-4-yl)-1H-pyrazol-4-yl]-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(100 mg) as brown solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and (1-(1-tert-(butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl) boronic acid (136 mg, 0.46 mmol)according to method in example 1, step 1h.

Step 17b: Preparation of9-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

9-(1-(1-tert-(butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl]-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (60mg) as yellow solid was prepared by using ethyl9-(1-(1-(tert-butoxycarbonyl)-piperidin-4-yl)-1H-pyrazol-4-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]-isoquinoline-3-carboxylate(100 mg, 0.17 mmol) according to method in example 1, step 1i.

Step 17c: Preparation of6-(tert-butyl)-10-methoxy-2-oxo-9-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid Hydrochloride

To a solution of9-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (60 mg, 0.1 mmol) in dioxane was added 1 M HCl solution (5 mL), andthe reaction mixture was stirred at RT for 1 h, concentrated to provide6-(tert-butyl)-10-methoxy-2-oxo-9-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid hydrochloride (47.8 mg) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆):δ 8.76 (s, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.75 (s, 1H), 7.59 (s, 1H),7.58 (s, 1H), 4.62-4.54 (m, 2H), 4.00 (s, 3H), 3.39-3.33 (m, 2H),3.30-3.26 (m, 2H), 3.07 (s, 2H), 2.20 (s, 4H), 0.73 (s, 9H). MS observed(ESI⁺) [(M+H)⁺]: 477.

Example 186-(tert-butyl)-9-(1-isopropyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 18a: Preparation of ethyl6-(tert-butyl)-9-(1-isopropyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(1-isopropyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(80 mg) as off-white solid was prepared by using ethyl9-bromo-6-(tert-butyl)-1-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]-isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(60 mg, 0.253 mmol) according to method in example 16, step 16a.

Step 18b: Preparation of6-(tert-butyl)-9-(1-isopropyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(1-isopropyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (35.7 mg) as white solid was prepared by using ethyl6-(tert-butyl)-9-(1-isopropyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(80 mg, 0.17 mmol) according to method in example 16, step 16b. ¹H NMR(400 MHz, DMSO-d₆): δ 16.47 (s, 1H), 8.79 (s, 1H), 7.69 (s, 1H), 7.68(s, 1H), 7.52 (s, 1H), 7.35 (s, 1H), 6.24-6.23 (m, 1H), 4.64-4.63 (m,1H), 4.17-4.10 (m, 1H), 3.90 (s, 3H), 3.43-3.37 (m, 2H), 1.33-1.29 (m,6H), 0.74 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 436.

Example 196-(tert-butyl)-9-(1,4-dimethyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 19a: Preparation of ethyl6-(tert-butyl)-9-(1,4-dimethyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(1,4-dimethyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(40 mg) as brown solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(56 mg, 0.253 mmol) according to method in example 16, step 16a.

Step 19b: Preparation of6-(tert-butyl)-9-(1,4-dimethyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(1,4-dimethyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (7.7 mg) as light yellow solid was prepared by using ethyl6-(tert-butyl)-9-(1,4-dimethyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(40 mg, 0.089 mmol) according to method in example 16, step 16b. ¹H NMR(400 MHz, DMSO-d₆): δ 8.79 (s, 1H), 7.69 (s, 1H), 7.68 (s, 1H),7.33-7.32 (m, 2H), 4.65-4.64 (m, 1H), 3.91 (s, 3H), 3.57 (s, 3H),3.44-3.37 (m, 2H), 1.87 (s, 3H), 0.74 (s, 9H). MS observed (ESI⁺)[(M+H)⁺]: 422.

Example 206-(tert-butyl)-9-(1-carboxymethyl-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 20a: Preparation of ethyl6-(tert-butyl)-9-(1-(2-ethoxy-2-oxoethyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(1-(2-ethoxy-2-oxoethyl)-1H-pyrazol-4-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(30 mg) as white solid was prepared by using ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.12 mmol) and ethyl 2-bromoacetate (198 mg, 1.2 mmol) accordingto method in example 2, step 2a.

Step 20b: Preparation of6-(tert-butyl)-9-(1-carboxymethyl-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(1-carboxymethyl-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (11.3 mg) as white solid was prepared by using ethyl6-(tert-butyl)-9-(1-(2-ethoxy-2-oxoethyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(30 mg, 0.06 mmol) according to method in example 2, step 2b. ¹H NMR(400 MHz, DMSO-d₆): δ 8.76 (s, 1H), 8.26 (s, 1H), 8.02 (s, 1H), 7.74 (s,1H), 7.58 (s, 1H), 7.57 (s, 1H), 4.89 (s, 2H), 4.61 (d, J=6.0 Hz, 1H),4.00 (s, 3H), 3.45-3.43 (m, 2H), 0.74 (s, 9H). MS observed (ESI⁺)[(M+H)⁺]: 452.

Example 21 Ethyl6-(tert-butyl)-9-(1-(3-ethoxy-3-oxopropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Step 21: Preparation of ethyl6-(tert-butyl)-9-(1-(3-ethoxy-3-oxopropyl)-1H-pyrazolo-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(1-(3-ethoxy-3-oxopropyl)-1H-pyrazolo-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(312 mg) as white solid was prepared by using ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(400 mg, 0.95 mmol) and ethyl 3-bromopropionate (1.7 g, 95 mmol)according to method in example 2, step 2a. ¹H NMR (DMSO-d₆, 400 MHz): δ8.35 (s, 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.65 (s, 1H), 7.43 (s, 1H),7.03 (s, 1H), 4.41-4.35 (m, 2H), 4.22 (q, J=7.2 Hz, 2H), 4.08 (q, J=7.2Hz, 2H), 3.97 (s, 3H), 3.29-3.17 (m, 2H), 2.89 (t, J=6.8 Hz, 2H), 1.27(t, J=7.2 Hz, 3H), 1.16 (t, J=7.2 Hz, 3H), 0.73 (s, 9H). MS observed(ESI⁺) [(M+H)⁺]: 522.

Example 226-(tert-butyl)-9-(1-(2-carboxyethyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 22: Preparation of6-(tert-butyl)-9-(1-(2-carboxyethyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(1-(2-carboxyethyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (231.1 mg) as white solid was prepared by using ethyl6-(tert-butyl)-9-(1-(3-ethoxy-3-oxopropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(312 mg, 0.6 mmol) according to method in example 2, step 2b. ¹H NMR(400 MHz, DMSO-d₆): δ 16.63 (s, 1H), 12.41 (s, 1H), 8.76 (s, 1H), 8.26(s, 1H), 8.02 (s, 1H), 7.72 (s, 1H), 7.59 (s, 1H), 7.57 (s, 1H), 4.61(d, J=6.0 Hz, 1H), 4.36 (t, J=6.4 Hz, 2H), 4.00 (s, 3H), 3.44-3.37 (m,1H), 3.30-3.25 (m, 1H), 2.83 (t, J=6.8 Hz, 2H), 0.73 (s, 9H). MSobserved (ESI⁺) [(M+H)⁺]: 466.

Example 236-(tert-butyl)-9-(1-(3-ethoxy-3-oxopropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 23: Preparation of6-(tert-butyl)-9-(1-(3-ethoxy-3-oxopropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(1-(3-ethoxy-3-oxopropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (7.1 mg) as white solid was prepared by using6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (60 mg, 0.15 mmol) and ethyl 3-bromopropionate (276 mg, 1.5 mmol)according to method in example 2, step 2a. ¹H NMR (400 MHz, DMSO-d₆): δ16.62 (s, 1H), 8.76 (s, 1H), 8.26 (s, 1H), 8.02 (s, 1H), 7.72 (s, 1H),7.59 (s, 1H), 7.57 (s, 1H), 4.61 (d, J=6.0 Hz, 1H), 4.40 (t, J=6.8 Hz,2H), 4.06 (q, J=7.2 Hz, 2H), 4.00 (s, 3H), 3.29-3.23 (m, 2H), 2.90 (t,J=6.4 Hz, 2H), 1.16 (t, J=7.2 Hz, 3H), 0.73 (s, 9H). MS observed (ESI⁺)[(M+H)⁺]: 494.

Example 246-(tert-butyl)-9-(1-(3-carboxypropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 24a: Preparation of ethyl6-(tert-butyl)-9-(1-(4-ethoxy-4-oxobutyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(1-(4-ethoxy-4-oxobutyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(30 mg) as yellow solid was prepared by using ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.12 mmol) and ethyl 4-bromobutyrate (232 mg, 1.2 mmol)according to method in example 2, step 2a.

Step 24b: Preparation of6-(tert-butyl)-9-(1-(3-carboxypropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(1-(3-carboxypropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (15.2 mg) as yellow solid was prepared by using ethyl6-(tert-butyl)-9-(1-(4-ethoxy-4-oxobutyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(30 mg, 0.06 mmol) according to method in example 2, step 2b. ¹H NMR(400 MHz, DMSO-d₆): δ 8.76 (s, 1H), 8.26 (s, 1H), 8.03 (s, 1H), 7.73 (s,1H), 7.58 (s, 1H), 7.57 (s, 1H), 4.61 (d, J=6.0 Hz, 1H), 4.17 (t, J=6.8Hz, 2H), 4.00 (s, 3H). 3.43-3.42 (m, 2H), 2.24-2.18 (m, 2H), 2.05-2.00(m, 2H), 0.73 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 480.

Example 256-(tert-butyl)-10-methoxy-9-(3-methyl-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 25a: Preparation of3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a solution of3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.0 gm 4.81 mmol) in CH₃CN (20 mL) was added di-tert-butyl dicarbonate(1.26 g, 5.77 mmol) and trimethylamine (730 mg, 7.21 mmol) undernitrogen, and the reaction mixture was stirred at RT for 16 h. TLCshowed that the starting material was completely consumed. Then, themixture was concentrated under reduced pressure and purified by flashcolumn chromatography to provide3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.2 g) as light yellow solid.

Step 25b: Preparation of ethyl9-(1-tert-butoxycarbonyl-3-methyl-1H-pyrazol-4-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl9-(1-tert-butoxycarbonyl-3-methyl-1H-pyrazol-4-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(140 mg) as orange solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(150 mg, 0.345 mmol) and3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(128 mg, 0.414 mmol) according to method in example 16, step 16a.

Step 25c: Preparation of6-(tert-butyl)-10-methoxy-9-(3-methyl-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-9-(3-methyl-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (10 mg) as white solid was prepared by using ethyl9-(1-tert-butoxycarbonyl-3-methyl-1H-pyrazol-4-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(140 mg, 0.261 mmol) according to method in example 16, step 16b. ¹H NMR(400 MHz, DMSO-d₆): δ 16.62 (s, 1H), 8.76 (s, 1H), 7.60 (s, 1H), 7.56(s, 1H), 7.33 (s, 1H), 4.61 (d, J=5.6 Hz, 1H), 3.90 (s, 3H), 3.43-3.35(m, 2H), 2.56 (s, 3H), 0.74 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 408.

Example 266-(tert-butyl)-9-(1-(1-carboxyethyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 26a: Preparation of ethyl6-(tert-butyl)-9-(1-(1-ethoxy-1-oxoprop-2-yl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(1-(1-ethoxy-1-oxoprop-2-yl)-1H-pyrazol-4-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(20 mg) as white solid was prepared by using ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.12 mmol) and ethyl 2-bromopropionate (215 mg, 1.2 mmol)according to method in example 2, step 2a.

Step 26b: Preparation of6-(tert-butyl)-9-(1-(1-carboxyethyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(1-(1-carboxyethyl)-1H-pyrazol-4-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (7.6 mg) as white solid was prepared by using ethyl6-(tert-butyl)-9-(1-(1-ethoxy-1-oxopropyl-2-yl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(20 mg. 0.04 mmol) according to method in example 2, step 2b. ¹H NMR(400 MHz, DMSO-d₆): δ 8.75 (s, 1H), 8.32 (s, 1H), 8.02 (s, 1H), 7.74 (s,1H), 7.59 (s, 1H), 7.57 (s, 1H), 5.11 (d, J=7.2 Hz, 1H), 4.61 (d, J=6.0Hz, 1H), 4.00 (s, 3H), 3.43-3.39 (m, 2H), 1.67 (d, J=7.6 Hz, 3H), 0.74(s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 466.

Example 276-(tert-butyl)-9-(1-(2-carboxyprop-2-yl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 27a: Preparation of ethyl6-(tert-butyl)-9-(1-(1-ethoxy-2-methyl-1-oxoprop-2-yl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(1-(1-ethoxy-2-methyl-1-oxoprop-2-yl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(20 mg) as yellow solid was prepared by using ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.12 mmol) and ethyl 2-bromo-2-methylpropionate (232 mg, 1.2mmol) according to method in example 2, step 2a.

Step 27b: Preparation of6-(tert-butyl)-9-(1-(2-carboxyprop-2-yl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(1-(2-carboxyprop-2-yl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (11.8 mg) as yellow solid was prepared by using ethyl6-(tert-butyl)-9-(1-(1-ethoxy-2-methyl-1-oxoprop-2-yl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(20 mg, 0.04 mmol) according to method in example 2, step 2b. ¹H NMR(400 MHz, DMSO-d₆): δ 8.76 (s, 1H), 8.35 (s, 1H), 8.04 (s, 1H), 7.76 (s,1H), 7.59 (s, 1H), 7.58 (s, 1H), 4.61 (d, J=6.0 Hz, 1H), 4.00 (s, 3H),3.44-3.40 (m, 2H), 1.78 (s, 6H), 0.74 (s, 9H). MS observed (ESI⁺)[(M+H)⁺]: 480.

Example 286-(tert-butyl)-10-methoxy-9-(2-methylthiazol-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 28a: Preparation of ethyl6-(tert-butyl)-10-methoxy-9-(2-methylthiazol-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

To a solution of ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.23 mmol) in toluene (50 mL) and water (5 mL) was added(2-methylthiazol-5-yl)boronic acid (49 mg, 0.35 mmol), sodium carbonate(49 mg, 0.46 mmol) and Pd(PPh₃)₄(13 mg, 0.01 mmol) under nitrogenatmosphere, and the reaction mixture was allowed to heat at reflux for16 h. Then, the reaction mixture was partitioned between DCM (20 mL) andwater (30 mL), and the organic phase was washed with brine, dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure, the resulted residue was purified by preparative TLC toprovide ethyl6-(tert-butyl)-10-methoxy-9-(2-methylthiazol-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate (10 mg) as white solid.

Step 28b: Preparation of6-(tert-butyl)-10-methoxy-9-(2-methylthiazol-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-9-(2-methylthiazol-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (7.6 mg) as yellow solid was prepared by using ethyl6-(tert-butyl)-10-methoxy-9-(2-methylthiazol-5-yl)-2-oxo-6,7-dihydro-2H-pyrido-[2,1-a]isoquinoline-3-carboxylate(10 mg, 0.03 mmol) according to method in example 1, step 1i. ¹H NMR(400 MHz, DMSO-d₆): δ 16.52 (s, 1H), 8.78 (s, 1H), 8.26 (s, 1H), 7.89(s, 1H), 7.69 (s, 1H), 7.67 (s, 1H), 4.64 (d, J=5.2 Hz, 1H), 4.03 (s,3H), 3.41-3.36 (m, 2H), 2.68 (s, 3H), 0.74 (s, 9H). MS observed (ESI⁺)[(M+H)⁺]: 425.

Example 296-(tert-butyl)-10-methoxy-2-oxo-9-(1H-1,2,4-triazol-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 29a: Preparation of6-(tert-butyl)-9-cyano-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

To a solution of ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(1.6 g, 3.68 mmol) in NMP (20 mL) was added CuCN (660 mg, 7.37 mmol),and the reaction mixture was heated at 150° C. for 16 h. Then, themixture was concentrated under reduced pressure, and the resultedresidue was purified by column chromatography to provide6-(tert-butyl)-9-cyano-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (1.2 g).

Step 29b: Preparation of6-(tert-butyl)-9-carbamoyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

To a solution of6-(tert-butyl)-9-cyano-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (1.3 g, 3.42 mmol) was added dropwise con. Sulfuric acid (20 mL),and the reaction mixture was allowed to heat at reflux for 1 h. Then,the mixture was slowly added to ice-water (100 mL), extracted with DCM(200 mL), and the organic phase was washed with brine (100 mL), driedover anhydrous sodium sulfate, filtered and concentrate under reducepressure, the resulted residue was purified by column chromatography toprovide6-(tert-butyl)-9-carbamoyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (800 mg) as white solid.

Step 29c: Preparation of methyl6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-1,2,4-triazol-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

A solution of6-(tert-butyl)-9-carbamoyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (800 mg, 2.16 mmol) in DMF-DMAc (5 mL) was allowed to heat atreflux for 1 h. Then, the volatiles were evaporated and the resultedresidue was dissolved into EtOH (5 mL) ready for next stage. Hydrazinehydrate (0.6 mL) was added slowly to a mixture of EtOH (25 mL) andacetic acid (6 mL) at ice-bath, then, to this solution was added theEtOH solution (5 mL) prepared from previous stage, and the reactionmixture was allowed to stir at RT for 16 h. The mixture was partitionedbetween DCM (100 mL) and water (100 mL), and the organic phase waswashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure, the resulted residue was purifiedby column chromatography to provide methyl6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-1,2,4-triazol-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(370 mg) as white solid.

Step 29d: Preparation of6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-1,2,4-triazol-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-1,2,4-triazol-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (5.3 mg) as white solid was prepared by using methyl6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-1,2,4-triazol-3-yl)-6,7-dihydro-2H-pyrido-[2,1-a]isoquinoline-3-carboxylate(20 mg, 0.05 mmol) according to method in example 2, step 2b. ¹H NMR(400 MHz, DMSO-d₆): δ 16.46 (s, 1H), 13.93 (s, 1H), 8.80 (s, 1H), 8.16(s, 1H), 8.09 (s, 1H), 7.74 (s, 1H), 7.72 (s, 1H), 4.66 (s, 1H), 4.09(s, 3H), 3.44 (s, 2H), 0.73 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 395.

Example 306-(tert-butyl)-9-(1-(carboxymethyl)-1H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 30a: Preparation of methyl6-(tert-butyl)-9-(1-(2-ethoxy-2-oxoethyl)-1H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

To a solution of methyl6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-1,2,4-triazol-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(40 mg, 0.1 mmol) in DMF (1 mL) was added ethyl 2-bromoacetate (163 mg,1 mmol) and K₂CO₃ (136 mg, 1 mmol), and the reaction mixture was allowedto stir at RT for 16 h. Then, the mixture was partitioned between DCM(10 mL) and water (5 mL), the water phase was extracted with DCM (10mL×2), and the combined organic phase was washed with brine (10 mL×3),dried over anhydrous sodium sulfate, filtered and concentrated, and theresulted residue was purified by preparative TLC to give methyl6-(tert-butyl)-9-(1-(2-ethoxy-2-oxoethyl)-1H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(30 mg) as white solid.

Step 30b: Preparation of6-(tert-butyl)-9-(1-(carboxymethyl)-1H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(1-(carboxymethyl)-1H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (2.5 mg) as white solid was prepared by using methyl6-(tert-butyl)-9-(1-(2-ethoxy-2-oxoethyl)-1H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(30 mg, 0.06 mmol) according to method in example 2, step 2b. ¹H NMR(400 MHz, DMSO-d₆): δ 16.53 (s, 1H), 8.79 (s, 1H), 8.57 (s, 1H), 7.86(s, 1H), 7.67 (s, 1H), 7.66 (s, 1H), 5.09 (s, 2H), 4.64 (s, 1H), 3.93(s, 3H), 3.42-3.39 (m, 2H), 0.73 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]:453.

Example 316-(tert-butyl)-9-(4-(3-hydroxypropyl)-4H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Example 326-(tert-butyl)-9-(1-(3-hydroxypropyl)-1H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 31: Preparation of methyl6-(tert-butyl)-9-(4-(3-hydroxypropyl)-4H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylateand methyl6-(tert-butyl)-9-(1-(3-hydroxypropyl)-1H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

To a solution of methyl6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-1,2,4-triazol-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.25 mmol) in CH₃CN (3 mL) was added 3-bromo-1-propanol (300mg, 2.45 mmol) and K₂CO₃ (348 mg, 2.5 mmol), and the reaction mixturewas allowed to stir at RT for 16 h. Water (5 mL) was added to themixture, and extract with DCM (10 mL×3), the combined organic phase waswashed with brine (10 mL×3), dried over anhydrous sodium sulfate,filtered and concentrated, the resulted residue was purified bypreparative TLC to provide methyl6-(tert-butyl)-9-(4-(3-hydroxypropyl)-4H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]-isoquinoline-3-carboxylate(20 mg) and methyl6-(tert-butyl)-9-(1-(3-hydroxypropyl)-1H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg) as white solid.

Step 32a: Preparation of 6-(tert-butyl)-9-(4-(3-hydroxypropyl)-4H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(4-(3-hydroxypropyl)-4H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (9.7 mg) as white solid was prepared by using methyl6-(tert-butyl)-9-(4-(3-hydroxypropyl)-4H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(20 mg, 0.04 mmol) according to method in example 2, step 2b. ¹H NMR(400 MHz, DMSO-d₆): δ 16.43 (s, 1H), 8.80 (s, 1H), 8.06 (s, 1H), 7.74(s, 2H), 7.49 (s, 1H), 4.66 (d, J=3.6 Hz, 1H), 4.47 (s, 1H), 3.99 (t,J=7.2 Hz, 2H), 3.93 (s, 3H), 3.41-3.38 (m, 4H), 1.89-1.82 (m, 2H), 0.74(s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 453.

Step 32b: Preparation of6-(tert-butyl)-9-(1-(3-hydroxypropyl)-1H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(1-(3-hydroxypropyl)-1H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (39.5 mg) as white solid was prepared by using methyl6-(tert-butyl)-9-(1-(3-hydroxypropyl)-1H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.11 mmol) according to method in example 2, step 2b. ¹H NMR(400 MHz, DMSO-d₆): δ 8.79 (s, 1H), 8.59 (s, 1H), 7.83 (s, 1H), 7.67 (s,1H), 7.66 (s, 1H), 4.65 (s, 1H), 4.29 (t, J=6.8 Hz, 2H), 3.93 (s, 3H),3.47-3.41 (m, 4H), 1.97 (q, J=6.4 Hz, 2H), 0.74 (s, 9H). MS observed(ESI⁺) [(M+H)⁺]: 453.

Example 336-(tert-butyl)-10-methoxy-2-oxo-9-phenyl-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 33a: Preparation of ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-phenyl-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-phenyl-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(36 mg) as brown solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and phenylboronic acid (84 mg, 0.69 mmol) accordingto method in example 1, step 1h.

Step 33b: Preparation of6-(tert-butyl)-10-methoxy-2-oxo-9-phenyl-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-2-oxo-9-phenyl-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (16 mg) as brown solid was prepared by using ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-phenyl-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(36 mg, 0.083 mmol) according to method in example 1, step 1i. ¹H NMR(400 MHz, DMSO-d₆): δ 8.49 (s, 1H), 7.56-7.51 (m, 3H), 7.45-7.41 (m,3H), 7.38-7.34 (m, 2H), 4.45-4.41 (m, 1H), 3.88 (s, 3H), 3.24-3.18 (m,2H), 0.75 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 404.

Example 346-(tert-butyl)-9-(4-ethylphenyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 34a: Preparation of ethyl6-(tert-butyl)-9-(4-ethylphenyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(4-ethylphenyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]-isoquinoline-3-carboxylate(36 mg) as brown solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(70 mg, 0.16 mmol) and 4-ethylphenylboronic acid (72 mg, 0.48 mmol)according to method in example 1, step 1h.

Step 34b: Preparation of6-(tert-butyl)-9-(4-ethylphenyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(4-ethylphenyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (20 mg) as brown solid was prepared by using ethyl6-(tert-butyl)-9-(4-ethylphenyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate (36 mg, 0.078 mmol) according to methodin example 1, step 1i. ¹H NMR (400 MHz, DMSO-d₆): δ 8.78 (s, 1H), 7.65(s, 1H), 7.62 (s, 1H), 7.47 (d, J=8.0 Hz, 2H), 7.40 (s, 1H), 7.28 (d,J=8.0 Hz, 2H), 4.65-4.62 (m, 1H), 3.89 (s, 3H), 3.44-3.33 (m, 2H), 2.65(q, J=7.6 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H), 0.75 (s, 9H). MS observed(ESI⁺) [(M+H)⁺]: 432.

Example 356-(tert-butyl)-10-methoxy-9-(4-methoxyphenyl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 35a: Preparation of ethyl6-(tert-butyl)-10-methoxy-9-(4-methoxyphenyl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-10-methoxy-9-(4-methoxyphenyl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(15 mg) as brown solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquino-line-3-carboxylate(70 mg, 0.16 mmol) and 4-methoxyphenylboronic acid (73 mg, 0.48 mmol)according to method in example 1, step 1h.

Step 35b: Preparation of6-(tert-butyl)-10-methoxy-9-(4-methoxyphenyl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-9-(4-methoxyphenyl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (1.5 mg) as light yellow solid was prepared by using ethyl6-(tert-butyl)-10-methoxy-9-(4-methoxyphenyl)-2-oxo-6,7-dihydro-2H-pyrido-[2,1-a]isoquinoline-3-carboxylate(15 mg, 0.033 mmol) according to method in example 1, step 1i. ¹H NMR(400 MHz, DMSO-d₆): δ 8.76 (s, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 7.49 (d,J=8.8 Hz, 2H), 7.37 (s, 1H), 6.98 (d, J=8.8 Hz, 2H), 4.63-4.59 (m., 1H),3.87 (s, 3H), 3.78 (s, 3H), 3.74-3.70 (m, 1H), 3.68-3.62 (m, 1H), 0.73(s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 434.

Example 366-(tert-butyl)-10-methoxy-9-(3-methoxyphenyl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 36a: Preparation of ethyl6-(tert-butyl)-10-methoxy-9-(3-methoxyphenyl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

ethyl6-(tert-butyl)-10-methoxy-9-(3-methoxyphenyl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(20 mg) as brown solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(70 mg, 0.16 mmol) and 3-methoxyphenylboronic acid (73 mg, 0.48 mmol)according to method in example 1, step 1h.

Step 36b: Preparation of6-(tert-butyl)-10-methoxy-9-(3-methoxyphenyl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-9-(3-methoxyphenyl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (3.3 mg) as light yellow solid was prepared by using ethyl6-(tert-butyl)-9-(3-methoxyphenyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido-[2,1-a]isoquinoline-3-carboxylate(20 mg, 0.043 mmol) according to method in example 1, step 1i. ¹H NMR(400 MHz, DMSO-d₆): δ 8.77 (s, 1H), 7.64 (s, 1H), 7.61 (s, 1H), 7.41 (s,1H), 7.36-7.31 (m, 1H), 7.09-7.05 (m, 2H), 6.93 (d, J=7.2 Hz, 1H),4.63-4.58 (m, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.75-3.63 (m, 2H), 0.73(s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 434.

Example 376-(tert-butyl)-10-methoxy-9-(6-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 37: Preparation of6-(tert-butyl)-10-methoxy-9-(6-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

To a solution of ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.115 mmol) in DME (3 mL) and water (1 mL) was added(6-methylpyridin-3-yl)boronic acid (20.49 mg, 0.149 mmol), K₂CO₃ (23.9mg, 0.172 mmol) and Pd(PPh₃)₄(13.3 mg, 0.011 mmol), and the reactionmixture was exchanged with nitrogen three times, then, allowed to heatat 85° C. for 20 h. The reaction mixture was diluted with EtOAc (20 mL),and the organic phase was washed with water (30 mL) and brine (20 mL),dried over anhydrous sodium sulfate, filtered and concentrated, thenpurified by preparative TLC to provide6-(tert-butyl)-10-methoxy-9-(6-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (30 mg) as off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 16.52 (s,1H), 8.78 (s, 1H), 8.61 (s, 1H), 7.87-7.84 (m, 1H), 7.66 (s, 1H), 7.65(s, 1H), 7.47 (s, 1H), 7.33 (d, J=8.0 Hz, 1H), 4.64-4.63 (m, 1H), 3.91(s, 3H), 3.45-3.37 (m, 2H), 2.23 (s, 3H), 0.75 (s, 9H). MS observed(ESI⁺) [(M+H)⁺]: 419.

Example 386-(tert-butyl)-10-methoxy-9-(2-methylpyridin-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 38: Preparation of6-(tert-butyl)-10-methoxy-9-(2-methylpyridin-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-9-(2-methylpyridin-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (40 mg) as light yellow solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]-isoquinoline-3-carboxylate(50 mg, 0.115 mmol) and (2-methyl pyridin-4-yl)boronic acid (17.3 mg,0.127 mmol) according to method in example 37, step 37. ¹H NMR (400 MHz,DMSO-d₆): δ 16.49 (s, 1H), 8.79 (s, 1H), 8.48 (d, J=8.0 Hz, 1H), 7.69(s, 1H), 7.68 (s, 1H), 7.49 (s, 1H), 7.42 (s, 1H), 7.37-7.36 (m, 1H),4.65-4.64 (m, 1H), 3.92 (s, 3H), 3.45-3.34 (m, 2H), 2.52 (s, 3H), 0.75(s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 419.

Example 396-(tert-butyl)-10-methoxy-9-(2-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 39: Preparation of6-(tert-butyl)-10-methoxy-9-(2-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-9-(2-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (7.2 mg) as yellow solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]-isoquinoline-3-carboxylate(50 mg, 0.115 mmol) and (2-methylpyridin-3-yl)boronic acid (20 mg, 0.115mmol) according to method in example 37, step 37. ¹H NMR (400 MHz,DMSO-d₆): δ 8.78 (s, 1H), 8.47 (d, J=8.0 Hz, 1H), 7.67 (s, 1H), 7.65 (s,1H), 7.55 (d, J=8.0 Hz, 1H), 7.30-7.28 (m, 2H), 4.64-4.63 (m, 1H), 3.86(s, 3H), 3.44-3.42 (m, 2H), 2.26 (s, 3H), 0.75 (s, 9H). MS observed(ESI⁺) [(M+H)⁺]: 419.

Example 406-(tert-butyl)-10-methoxy-9-(6-morpholinylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 40: Preparation of6-(tert-butyl)-10-methoxy-9-(6-morpholinylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-9-(6-morpholinylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (27 mg) as yellow solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]-isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine(87 mg, 0.3 mmol) according to method in example 37, step 37. ¹H NMR(400 MHz, DMSO-d₆): δ 16.55 (s, 1H), 8.77 (s, 1H), 8.37 (s, 1H),7.81-7.79 (m, 1H), 7.62 (s, 1H), 7.60 (s, 1H), 7.43 (s, 1H), 6.90 (d,J=8.0 Hz, 1H), 4.62-4.61 (m, 1H), 3.91 (s, 3H), 3.71 (t, J=4.0 Hz, 4H),3.50 (t, J=4.0 Hz, 4H), 3.39-3.35 (m, 2H), 0.75 (s, 9H). MS observed(ESI⁺) [(M+H)⁺]: 490.

Example 416-(tert-butyl)-10-methoxy-2-oxo-9-(6-trifluoromethylpyridin-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 41: Preparation of6-(tert-butyl)-10-methoxy-2-oxo-9-(6-trifluoromethylpyridin-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-2-oxo-9-(6-trifluoromethylpyridin-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (44 mg) as yellow solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and (6-trifluoromethylpyridin-3-yl)boronic acid (58mg, 0.3 mmol) according to method in example 37, step 37. ¹H NMR (400MHz, DMSO-d₆): δ 16.46 (s, 1H), 8.96 (s, 1H), 8.80 (s, 1H), 8.28 (d,J=8.0 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.71 (s, 1H), 7.59(s, 1H), 4.66-4.65 (m, 1H), 3.95 (s, 3H), 3.47-3.34 (m, 2H), 0.76 (s,9H). MS observed (ESI⁺) [(M+H)⁺]: 473.

Example 426-(tert-butyl)-10-methoxy-9-(6-(2-methoxyethoxy)pyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 42: Preparation of 6-(tert-butyl)-10-methoxy-9-(6-(2-methoxyethoxy)pyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-9-(6-(2-methoxyethoxy)pyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (30 mg) as white solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido-[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.115 mmol) and (6-(2-methoxy-ethoxy)pyridin-3-yl)boronic acid(30 mg, 0.15 mmol) according to method in example 37, step 37. ¹H NMR(400 MHz, DMSO-d₆): δ 16.53 (s, 1H), 8.77 (s, 1H), 8.35 (s, 1H),7.93-7.90 (m, 1H), 7.65 (s, 1H), 7.64 (s, 1H), 7.46 (s, 1H), 6.91 (d,J=8.4 Hz, 1H), 4.62 (s, 1H), 4.42 (t, J=4.4 Hz, 2H), 3.91 (s, 3H), 3.68(t, J=4.0 Hz, 2H), 3.38-3.36 (m, 2H), 3.31 (s, 3H), 0.75 (s, 9H). MSobserved (ESI⁺) [(M+H)⁺]: 479.

Example 436-(tert-butyl)-9-(6-(dimethylamino)pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 43: Preparation of 6-(tert-butyl)-9-(6-(dimethylamino)pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(6-(dimethylamino)pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (63.1 mg) as yellow solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.225 mmol) and (6-(dimethylamino)-pyridin-3-yl)boronic acid(50 mg, 0.3 mmol) according to method in example 37, step 37. ¹H NMR(400 MHz, DMSO-d₆): δ 16.58 (s, 1H), 8.76 (s, 1H), 8.33 (d, J=1.6 Hz,1H), 7.75 (dd, J=8.8, 2.0 Hz, 1H), 7.61 (s, 1H), 7.59 (s, 1H), 7.41 (s,1H), 6.70 (d, J=8.4 Hz, 1H), 4.61 (d, J=5.2 Hz, 1H), 3.90 (s, 3H),3.44-3.35 (m, 2H), 3.07 (s, 6H), 0.75 (s, 9H). MS observed (ESI⁺)[(M+H)⁺]: 448.

Example 446-(tert-butyl)-10-methoxy-2-oxo-9-(6-(pyrrolidin-1-yl)pyridin-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 44: Preparation of6-(tert-butyl)-10-methoxy-2-oxo-9-(6-(pyrrolidin-1-yl)pyridin-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-2-oxo-9-(6-(pyrrolidin-1-yl)pyridin-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (25 mg) as yellow solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and (6-(pyrrolidin-1-yl)pyridin-3-yl)boronic acid(58 mg, 0.3 mmol) according to method in example 37, step 37. ¹H NMR(400 MHz, DMSO-d₆): δ 8.75 (s, 1H), 8.29 (s, 1H), 7.76 (d, J=8.0 Hz,1H), 7.60 (s, 1H), 7.58 (s, 1H), 7.41 (s, 1H), 6.55 (d, J=8.0 Hz, 1H),4.61-4.60 (m, 1H), 3.90 (s, 3H), 3.53-3.43 (m, 6H), 2.02-1.96 (m, 4H),0.74 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 474.

Example 456-(tert-butyl)-10-methoxy-2-oxo-9-(6-(piperazin-1-yl)pyridin-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 45a: Preparation of ethyl9-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl9-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(96 mg) as brown solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)boronic acid (108mg, 0.35 mmol) according to method in example 1, step 1h.

Step 45b: Preparation of ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(6-(piperazin-1-yl)pyridin-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

To a solution of ethyl9-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(96 mg, 0.156 mmol) in DCM (2 mL) was added trifluoroacetic acid (0.5mL), and the reaction mixture was allowed to stir at RT for 2 h. LC-MSdetected that the reaction was finished. Then, the mixture wasconcentrated and dissolved into saturated sodium carbonate solution (20mL), extracted with EtOAc (20 mL×3), and the combined organic phase waswashed with water (20 mL×5), dried over anhydrous sodium sulfate,filtered and concentrated, then purified by column chromatography toprovide ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(6-(piperazin-1-yl)pyridin-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(61 mg) as yellow solid.

Step 45c: Preparation of6-(tert-butyl)-10-methoxy-2-oxo-9-(6-(piperazin-1-yl)pyridin-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-2-oxo-9-(6-(piperazin-1-yl)pyridin-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (25 mg) as yellow solid was prepared by using ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(6-(piperazin-1-yl)-pyridin-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(61 mg, 0.118 mmol) according to method in example 1, step 1i. ¹H NMR(400 MHz, DMSO-d₆): δ 8.77 (s, 1H), 8.38 (s, 1H), 7.82 (d, J=8.0 Hz,1H), 7.62 (s, 1H), 7.61 (s, 1H), 7.43 (s, 1H), 6.95 (d, J=8.0 Hz, 1H),4.63-4.61 (m, 1H), 3.91 (s, 3H), 3.68-3.61 (m, 6H), 3.08-3.03 (m, 4H),0.75 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 489.

Example 469-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 46a: Preparation of ethyl9-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

To a solution of ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(6-(piperazin-1-yl)pyridin-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.096 mmol) in DCE (2 mL) was added acetic anhydride (14.7 mg,0.144 mmol) ane trimethylamine (29 mg, 0.288 mmol), and the reactionmixture was allowed to stir at RT for 16 h. TLC showed that the reactionwas finished. Then, the mixture was concentrated and purified bypreparative TLC to provide ethyl9-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquino-line-3-carboxylate(40 mg) as yellow solid.

Step 46b: Preparation of9-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

9-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (12.2 mg) as yellow solid was prepared by using ethyl9-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(40 mg, 0.071 mmol) according to method in example 1, step 1i. ¹H NMR(400 MHz, DMSO-d₆): δ 8.76 (s, 1H), 8.37 (d, J=2.3 Hz, 1H), 7.80 (dd,J=8.8, 2.1 Hz, 1H), 7.62 (s, 1H), 7.60 (s, 1H), 7.43 (s, 1H), 6.92 (d,J=9.0 Hz, 1H), 4.63-4.60 (m, 1H), 3.90 (s, 3H), 3.66-3.49 (m, 10H), 2.06(s, 3H), 0.75 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 531.

Example 476-(tert-butyl)-10-methoxy-9-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 47a: Preparation of ethyl6-(tert-butyl)-10-methoxy-9-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

To a solution of ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(6-(piperazin-1-yl)pyridin-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate (50mg, 0.096 mmol) in MeOH (2 mL) was added paraformaldehyde (20 mg) andNaBH₃CN (18 mg, 0.288 mmol), and the reaction mixture was allowed toheat at 50° C. for 2 h. LC-MS detected that the reaction was finished,and the mixture was concentrated to afford a crude product (60 mg),which was used for next stage without further purification.

Step 47b: Preparation of6-(tert-butyl)-10-methoxy-9-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-9-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (12.2 mg) as yellow solid was prepared by using ethyl6-(tert-butyl)-10-methoxy-9-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(60 mg, 0.113 mmol) according to method in example 1, step 1i. ¹H NMR(400 MHz, DMSO-d₆): δ 16.56 (s, 1H), 8.77 (s, 1H), 8.37 (d, J=2.1 Hz,1H), 7.81 (dd, J=8.8, 2.1 Hz, 1H), 7.63 (s, 1H), 7.61 (s, 1H), 7.43 (s,1H), 6.96 (d, J=9.0 Hz, 1H), 4.63-4.61 (m, 1H), 3.91 (s, 3H), 3.69-3.62(m, 6H), 2.86-2.82 (m, 4H), 2.50 (s, 3H), 0.75 (s, 9H). MS observed(ESI⁺) [(M+H)⁺]: 503.

Example 486-(tert-butyl)-9-(6-fluoro-4-methylpyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 48a: Preparation of ethyl6-(tert-butyl)-9-(6-fluoro-4-methylpyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(6-fluoro-4-methylpyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate as off-white solidwas prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]-isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and (6-fluoro-4-methylpyridin-3-yl)boronic acid(46.4 mg, 0.3 mmol) according to method in example 16, step 16a.

Step 48b: Preparation of6-(tert-butyl)-9-(6-fluoro-4-methylpyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(6-fluoro-4-methylpyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (22.3 mg) as white solid was prepared by using ethyl6-(tert-butyl)-9-(6-fluoro-4-methylpyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylateaccording to method in example 16, step 16b. ¹H NMR (400 MHz, DMSO-d₆):δ 16.51 (s, 1H), 8.79 (s, 0.5H), 8.63 (s, 0.5H), 7.98 (s, 1H), 7.67 (d,J=11.2 Hz, 1H), 7.32-7.26 (m, 2H), 7.17 (s, 1H), 4.65 (s, 1H), 4.47 (s,1H), 3.84 (s, 3H), 3.65-3.50 (m, 1H), 2.14 (s, 3H), 0.75 (s, 9H). MSobserved (ESI⁺) [(M+H)⁺]: 479.

Example 496-(tert-butyl)-9-(6-fluoropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 49a: Preparation of ethyl6-(tert-butyl)-9-(6-fluoropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(6-fluoropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylateas brown solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and (6-fluoropyridin-3-yl) boronic acid (42 mg, 0.3mmol) according to method in example 16, step 16a.

Step 49b: Preparation of6-(tert-butyl)-9-(6-fluoropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(6-fluoropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (72 mg) as light yellow solid was prepared by using ethyl6-(tert-butyl)-9-(6-fluoropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylateaccording to method in example 16, step 16b. ¹H NMR (400 MHz, DMSO-d₆):δ 16.48 (s, 1H), 8.76 (s, 1H), 8.39 (d, J=2.8 Hz, 1H), 8.18-8.15 (m,1H), 7.66 (s, 1H), 7.65 (s, 1H), 7.49 (s, 1H), 7.26-7.23 (m, 1H), 4.61(d, J=5.6 Hz, 1H), 3.90 (s, 3H), 3.39-3.32 (m, 2H), 0.72 (s, 9H). MSobserved (ESI⁺) [(M+H)⁺]: 423.

Example 509-(6-(azetidin-1-yl)pyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 50: Preparation of9-(6-(azetidin-1-yl)pyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

To a solution of6-(tert-butyl)-9-(6-fluoropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (42.2 mg, 0.1 mmol) in NMP (3 mL) in sealed tube was addedazetidine hydrochloride (74.4 mg, 0.8 mmol and K₂CO₃ (165.6 mg, 1.2mmol), and the reaction mixture was allowed to heat at 130° C. for 16 h,then cooled to RT. Water (10 mL) was added to the reaction mixture, andwas extracted with EtOAc for three times, and the combined organic phasewas dried over anhydrous sodium sulfate, filtered, concentrated, andpurified by preparative TLC to provide9-(6-(azetidin-1-yl)pyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]-isoquinoline-3-carboxylicacid (13 mg) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 16.58 (s,1H), 8.76 (s, 1H), 8.28 (d, J=2.4 Hz, 1H), 7.74-7.71 (m, 1H), 7.61 (s,1H), 7.59 (s, 1H), 7.40 (s, 1H), 6.41 (d, J=8.8 Hz, 1H), 4.62 (d, J=5.6Hz, 1H), 3.98 (t, J=7.2 Hz, 4H), 3.89 (s, 3H), 3.39-3.36 (m, 2H),2.36-2.32 (m, 2H), 0.74 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 460.

Example 516-(tert-butyl)-9-(6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 51: Preparation of 6-(tert-butyl)-9-(6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (26.4 mg) as yellow solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido-[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.115 mmol) and (6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)boronicacid (33.5 mg, 0.15 mmol) according to method in example 37, step 37. ¹HNMR (400 MHz, DMSO-d₆): δ 16.50 (s, 1H), 8.68 (s, 1H), 8.26 (d, J=2.0Hz, 1H), 7.67 (d, J=10.0 Hz, 1H), 7.51 (s, 2H), 7.36 (s, 1H), 6.82 (d,J=8.8 Hz, 1H), 4.71 (d, J=4.0 Hz, 1H), 4.02-3.95 (m, 2H), 3.83 (s, 3H),3.70-3.58 (m, 2H), 3.10-3.01 (m, 3H), 1.98-1.88 (m, 2H), 1.75-1.68 (m,2H), 0.67 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 504.

Example 526-(tert-butyl)-9-(6-(cyclopropylmethylamino)pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 52: Preparation of 6-(tert-butyl)-9-(6-(cyclopropylmethylamino)pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(6-(cyclopropylmethylamino)pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (18.7 mg) was prepared by using6-(tert-butyl)-9-(6-fluoropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido-[2,1-a]isoquinoline-3-carboxylicacid (42.2 mg, 0.1 mmol) and cyclopropylmethylamine (56.8 mg, 0.8 mmol)in DMSO (3 mL) according to method in example 50, step 50. ¹H NMR (400MHz, DMSO-d₆): δ 16.52 (s, 1H), 8.68 (s, 1H), 8.12 (s, 1H), 7.57-7.47(m, 4H), 7.31 (s, 1H), 6.48 (d, J=9.2 Hz, 1H), 5.24 (s, 2H), 4.53 (d,J=4.8 Hz, 1H), 4.07-4.03 (m, 1H), 3.82 (s, 3H), 3.10-3.07 (m, 2H), 0.66(s, 9H), 0.40-0.32 (m, 3H), 0.16-0.12 (m, 2H). MS observed (ESI⁺)[(M+H)⁺]: 474.

Example 539-(6-(azetidin-1-yl)-4-methylpyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido2,1-a isoquinoline-3-carboxylic Acid

Step 53: Preparation of9-(6-(azetidin-1-yl)-4-methylpyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

9-(6-(azetidin-1-yl)-4-methylpyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (21.5 mg) was prepared by using6-(tert-butyl)-9-(6-fluoro-4-methylpyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido-[2,1-a]isoquinoline-3-carboxylicacid (43.6 mg, 0.1 mmol) and azetidine hydrochloride (74.4 mg, 0.8 mmol)according to method in example 50, step 50. ¹H NMR (400 MHz, DMSO-d₆): δ16.48 (s, 1H), 8.70 (s, 1H), 7.69 (s, 1H), 7.56 (s, 1H), 7.50 (s, 1H),7.13 (s, 1H), 6.22 (s, 1H), 5.24 (t, J=5.2 Hz, 2H), 4.56 (d, J=5.2 Hz,1H), 3.88 (t, J=8.0 Hz, 4H), 3.76 (s, 3H), 3.26-3.24 (m, 2H), 1.92 (s,3H), 0.66 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 474.

Example 549-(6-aminopyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 54: Preparation of9-(6-aminopyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

9-(6-aminopyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (21.3 mg) as yellow solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido-[2,1-a]-isoquinoline-3-carboxylate(50 mg, 0.115 mmol) and (6-aminopyridin-3-yl)boronic acid (20.7 mg, 0.15mmol) according to method in example 37, step 37. ¹H NMR (400 MHz,DMSO-d₆): δ 16.60 (s, 1H), 8.76 (s, 1H), 8.15 (d, J=1.6 Hz, 1H),7.68-7.66 (m, 1H), 7.61 (s, 1H), 7.58 (s, 1H), 7.40 (s, 1H), 6.56 (d,J=8.8 Hz, 1H), 6.34 (s, 2H), 4.61 (d, J=5.6 Hz, 1H), 3.89 (s, 3H),3.32-3.28 (m, 2H), 0.74 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 420.

Example 55 Ethyl6-(tert-butyl)-10-methoxy-9-(6-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Step 55: Preparation of ethyl6-(tert-butyl)-10-methoxy-9-(6-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-10-methoxy-9-(6-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(16.5 mg) as grey brown solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]-isoquinoline-3-carboxylate(50 mg, 0.115 mmol) and (6-methylpyridin-3-yl)boronic acid (17.5 mg,0.127 mmol) according to method in example 16, step 16a. ¹H NMR (400MHz, DMSO-d₆): δ 8.60 (s, 1H), 8.38 (s, 1H), 7.85-7.83 (m, 1H), 7.52 (s,1H), 7.42 (s, 1H), 7.33-7.32 (m, 1H), 7.12 (s, 1H), 4.37-4.36 (m, 1H),4.22 (q, J=8.0 Hz, 2H), 3.89 (s, 3H), 3.31-3.27 (m, 2H), 2.51 (s, 3H),1.27 (t, J=8.0 Hz, 3H), 0.74 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 447.

Example 566-(tert-butyl)-9-(6-(cyclobutylamino)pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 56: Preparation of6-(tert-butyl)-9-(6-(cyclobutylamino)pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(6-(cyclobutylamino)pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (12.5 mg) was prepared by using6-(tert-butyl)-9-(6-fluoropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (42.2 mg, 0.1 mmol) and cyclobutylamine (56.8 mg, 0.8 mmol) in DMSO(3 mL) according to method in example 50, step 50. ¹H NMR (400 MHz,DMSO-d₆): δ 16.54 (s, 1H), 8.72 (s, 1H), 8.15 (d, J=2.0 Hz, 1H),7.61-7.60 (m, 1H), 7.56 (s, 1H), 7.53 (s, 1H), 7.35 (s, 1H), 7.06 (s,1H), 6.46 (d, J=9.2 Hz, 1H), 4.58 (d, J=6.4 Hz, 1H), 4.29-4.23 (m, 1H),3.85 (s, 3H), 3.35-3.31 (m, 2H), 2.28-2.22 (m, 2H), 1.88-1.81 (m, 2H),1.67-1.60 (m, 2H), 0.70 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 474.

Example 579-(6-acetamidopyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 57a: Preparation of ethyl9-(6-aminopyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl9-(6-aminopyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(112 mg) as yellow solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]-isoquino-line-3-carboxylate(200 mg, 0.46 mmol) and (6-aminopyridin-3-yl)boronic acid (82.8 mg, 0.6mmol) according to method in example 16, step 16a.

Step 57b: Preparation of ethyl9-(6-acetamidopyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

To a solution of ethyl9-(6-aminopyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(44.7 mg, 0.1 mmol) and acetic anhydride (96.8 mg, 0.8 mmol) in EtOH wasadded trimethylamine (80.9 mg, 0.8 mmol), and the reaction mixture washeated at 60° C. and stirred for 16 h. Then, saturated NaHCO₃ solution(1 mL) was added to quench the reaction, and the mixture wasconcentrated to afford ethyl9-(6-acetamidopyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylateas crude product.

Step 57c: Preparation of9-(6-acetamidopyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

9-(6-acetamidopyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (9.2 mg) as white solid was prepared by using crude product ofethyl9-(6-acetamidopyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylateaccording to method in example 1, step 1i. ¹H NMR (400 MHz, DMSO-d₆): δ16.50 (s, 1H), 10.57 (s, 1H), 8.74 (s, 1H), 8.45 (d, J=2.8 Hz, 1H), 8.09(d, J=8.8 Hz, 1H), 7.95-7.92 (m, 1H), 7.62 (s, 1H), 7.60 (s, 1H), 7.45(s, 1H), 4.59 (d, J=4.8 Hz, 1H), 3.87 (s, 3H), 3.37-3.32 (m, 2H), 2.07(s, 3H), 0.70 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 462.

Example 586-(tert-butyl)-10-methoxy-9-(2-methylpyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 58: Preparation of6-(tert-butyl)-10-methoxy-9-(2-methylpyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-9-(2-methylpyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (19 mg) as light yellow solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]-isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and (2-methylpyrimidin-5-yl)boronic acid (32 mg,0.23 mmol) according to method in example 37, step 37. ¹H NMR (400 MHz,DMSO-d₆): δ 16.49 (s, 1H), 8.89 (s, 2H), 8.79 (s, 1H), 7.69 (s, 2H),7.56 (s, 1H), 4.65 (d, J=4.0 Hz, 1H), 3.93 (s, 3H), 3.46-3.40 (m, 2H),2.67 (s, 3H), 0.75 (s, 9H). MS observed (ESI⁺)[(M+H)⁺]: 420.

Example 596-(tert-butyl)-10-methoxy-2-oxo-9-(2-(pyrrolidin-1-yl)pyrimidin-5-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 59a: Preparation of ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(2-(pyrrolidin-1-yl)pyrimidin-5-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(2-(pyrrolidin-1-yl)pyrimidin-5-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(98 mg) as brown solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and (2-(pyrrolidin-2-yl)pyrimidin-5-yl)boronic acid(68 mg, 0.35 mmol) according to method in example 1, step 1h.

Step 59b: Preparation of6-(tert-butyl)-10-methoxy-2-oxo-9-(2-(pyrrolidin-1-yl)pyrimidin-5-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-2-oxo-9-(2-(pyrrolidin-1-yl)pyrimidin-5-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (53.3 mg) as yellow solid was prepared by using ethyl6-(tert-butyl)-10-methoxy-2-oxo-9-(2-(pyrrolidin-1-yl)pyrimidin-5-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(98 mg, 0.195 mmol) according to method in example 1, step 1i. ¹H NMR(400 MHz, DMSO-d₆): δ 16.54 (s, 1H), 8.77 (s, 1H), 8.58 (s, 2H), 7.63(s, 1H), 7.62 (s, 1H), 7.46 (s, 1H), 4.63-4.61 (m, 1H), 3.92 (s, 3H),3.55-3.48 (m., 4H), 3.39 (d, J=6.2 Hz, 2H), 1.98-1.92 (m., 4H), 0.75 (s,9H). MS observed (ESI⁺) [(M+H)⁺]: 475.

Example 606-(tert-butyl)-10-methoxy-9-(2-(methylamino)pyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 60a: Preparation of methyl6-(tert-butyl)-10-methoxy-9-(2-(methylamino)pyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Methyl6-(tert-butyl)-10-methoxy-9-(2-(methylamino)pyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(20 mg) as brown solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and (2-(methylamino)pyrimidin-5-yl)boronic acid (39mg, 0.25 mmol) according to method in example 1, step 1h.

Step 60b: Preparation of 6-(tert-butyl)-10-methoxy-9-(2-(methylamino)pyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-9-(2-(methylamino)pyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido-[2,1-a]isoquinoline-3-carboxylicacid (11.2 mg) as yellow solid was prepared by using methyl6-(tert-butyl)-10-methoxy-9-(2-(methylamino)pyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(20 mg, 0.04 mmol) according to method in example 1, step 1i. ¹H NMR(400 MHz, DMSO-d₆): δ 16.54 (s, 1H), 8.77 (s, 1H), 8.53 (s, 2H), 7.63(s, 1H), 7.61 (s, 1H), 7.46 (s, 1H), 7.29 (s, 1H) 4.62 (d, J=5.6 Hz,1H), 3.92 (s, 3H), 3.38 (d, J=6.0 Hz, 2H), 2.85 (d, J=4.4 Hz, 3H), 0.75(s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 435.

Example 616-(tert-butyl)-9-(2-(dimethylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 61a: Preparation of methyl 6-(tert-butyl)-9-(2-(dimethylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Methyl6-(tert-butyl)-9-(2-(dimethylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(18 mg) as brown solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and (2-(dimethylamino)-pyrimidin-5-yl)boronic acid(43 mg, 0.25 mmol) according to method in example 1, step 1h.

Step 61b: Preparation of6-(tert-butyl)-9-(2-(dimethylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(2-(dimethylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (10.1 mg) as yellow solid was prepared by using methyl6-(tert-butyl)-9-(2-(dimethylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(18 mg, 0.04 mmol) according to method in example 1, step 1i. ¹H NMR(400 MHz, DMSO-d₆): δ 8.77 (s, 1H), 8.59 (s, 2H), 7.63 (s, 1H), 7.62 (s,1H), 7.60-7.44 (m, 1H), 4.62 (s, 1H), 3.92 (s, 3H), 3.39-3.35 (m, 2H),3.17 (s, 6H), 0.75 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 449.

Example 626-(tert-butyl)-10-methoxy-9-(2-morpholinylpyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 62a: Preparation of methyl6-(tert-butyl)-10-methoxy-9-(2-morpholinylpyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Methyl6-(tert-butyl)-10-methoxy-9-(2-morpholinylpyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(20 mg) as brown solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and (2-morpholinyl-pyrimidin-5-yl)boronic acid (53mg, 0.25 mmol) according to method in example 1, step 1h.

Step 62b: Preparation of6-(tert-butyl)-10-methoxy-9-(2-morpholinyl-pyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-9-(2-morpholinylpyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (13.5 mg) as yellow solid was prepared by using methyl6-(tert-butyl)-10-methoxy-9-(2-morpholinylpyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(20 mg, 0.04 mmol) according to method in example 1, step 1i. ¹H NMR(400 MHz, DMSO-d₆): δ 8.77 (s, 1H), 8.63 (s, 2H), 7.64 (s, 1H), 7.63 (s,1H), 7.48 (s, 1H), 4.62 (d, J=6.0 Hz, 1H), 3.92 (s, 3H), 3.78-3.74 (m,4H), 3.70-3.66 (m, 4H), 3.39 (d, J=6.4 Hz, 2H), 0.75 (s, 9H). MSobserved (ESI⁺) [(M+H)⁺]: 491.

Example 636-(tert-butyl)-9-(2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 63: Preparation of ethyl6-(tert-butyl)-9-(2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

To a solution of ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.115 mmol) in dioxane (5 mL) and MeOH (3 mL) was added(2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)boronic acid (26.8 mg, 0.15mmol), PdCl₂(dppf) (16.8 mg, 0.023 mmol) and K₃PO₄ (37 mg, 0.175 mmol),and the mixture was exchanged with nitrogen three times, followed byheating at 90° C. and stirred for 18 h. The reaction mixture was dilutedwith EtOAc (20 mL), washed with water (30 mL) and brine (20 mL), and theorganic phase was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure, the resulted residue was purifiedby preparative TLC to provide ethyl6-(tert-butyl)-9-(2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylateas off-yellow solid.

Step 64: Preparation of 6-(tert-butyl)-9-(2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (51.6 mg) as yellow solid was prepared by using ethyl6-(tert-butyl)-9-(2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylateaccording to method in example 1, step 1i. ¹H NMR (400 MHz, DMSO-d₆): δ16.55 (s, 1H), 8.77 (s, 1H), 8.63 (s, 2H), 7.64 (s, 1H), 7.63 (s, 1H),7.49 (s, 1H), 5.33-5.30 (m, 1H), 4.63 (d, J=6.0 Hz, 2H), 3.92 (s, 3H),2.55 (d, J=7.2 Hz, 2H), 2.36-2.30 (m, 2H), 2.21-2.14 (m, 2H), 2.00-1.97(m, 4H), 0.85 (t, J=6.4 Hz, 3H), 0.74 (s, 9H). MS observed (ESI⁺)[(M+H)⁺]: 518.

Example 646-(tert-butyl)-9-(2-(cyclopropylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Example 659-(2-aminopyrimidin-5-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 65: Preparation of6-(tert-butyl)-9-(2-(cyclopropylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid and9-(2-aminopyrimidin-5-yl)-6-(tert-butyl)-1-methoxy-2-oxo-6,7-dihydro-2H-pyrido-[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(2-(cyclopropylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (2.4 mg) as light yellow solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.115 mmol) and (2-cyclopropylaminopyrimidin-5-yl)boronic acid(26.9 mg, 0.15 mmol) according to method in example 37, step 37. ¹H NMR(400 MHz, DMSO-d₆): δ 16.50 (s, 1H), 8.71 (s, 1H), 8.49 (s, 2H), 7.57(s, 1H), 7.55 (s, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 4.57 (d, J=5.6 Hz,1H), 3.87 (s, 3H), 3.38-3.32 (m, 2H), 2.70-2.66 (m, 1H), 0.69 (s, 9H),0.65-0.60 (m, 2H), 0.46-0.42 (m, 2H). MS observed (ESI⁺) [(M+H)⁺]: 461.

And9-(2-aminopyrimidin-5-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (16.1 mg) was obtained as light yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 16.50 (s, 1H), 8.69 (s, 1H), 8.41 (s, 2H), 7.55 (s, 1H),7.53 (s, 1H), 7.40 (s, 1H), 6.77 (s, 2H), 4.56 (d, J=6.8 Hz, 1H), 3.85(s, 3H), 3.45-3.42 (m, 2H), 0.67 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]:421.

Example 666-(tert-butyl)-10-methoxy-9-(2-methoxypyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 66a: Preparation of ethyl6-(tert-butyl)-9-(2-chloropyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(2-chloropyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylateas brown solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate (50 mg, 0.115 mmol) and(2-chloropyrimidin-5-yl) boronic acid (23.7 mg, 0.15 mmol) according tomethod in example 37, step 37.

Step 66b: Preparation of6-(tert-butyl)-10-methoxy-9-(2-methoxypyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

To a solution of ethyl6-(tert-butyl)-9-(2-chloropyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylatein MeOH (3 mL) and water (1 mL) was added lithium hydroxide monohydrate(19.3 mg, 0.46 mmol), and the mixture was stir at RT for 1 h. Then, themixture was concentrated, and the residue was dissolved in water (20mL), extracted with EtOAc (20 mL×5), the water phase was acidified with1M HCl till pH=2, and extracted with EtOAc (10 mL×5), and the combinedorganic phase was washed with water (20 mL×5), and then concentrated toprovide6-(tert-butyl)-10-methoxy-9-(2-methoxypyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (28.7 mg) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 16.44 (s,1H), 8.76 (s, 2H), 8.72 (s, 1H), 7.61 (s, 1H), 7.60 (s, 1H), 7.48 (s,1H), 4.57 (d, J=4.4 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.32-3.28 (m,2H), 0.68 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 436.

Example 676-(tert-butyl)-9-(2-(cylcopropylmethylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 67a: Preparation of (2-((cyclopropylmethyl)amino)pyrimidin-5-yl)boronic Acid

To a solution of (2-chloropyrimidin-5-yl)boronic acid (100 mg, 0.63mmol) in CH₃CN (4 mL) was added cyclopropylmethylamine (179.2 mg, 2.52mmol) under nitrogen, and the mixture was allowed to heat at 80° C. andstirred for 16 h. LC-MS showed the reaction was completed. Then, themixture was concentrated to dryness to provide(2-((cyclopropylmethyl)amino)pyrimidin-5-yl)boronic acid (200 mg) ascrude product, which was directly used for next stage without furtherpurification.

Step 67b: Preparation of ethyl6-(tert-butyl)-9-(2-(cylcopropylmethylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(2-(cylcopropylmethylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(53 mg) as brown solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(200 mg, 0.46 mmol) and (2-((cyclopropylmethyl)amino)pyrimidin-5-yl)boronic acid (177.6 mg, 0.92 mmol) according tomethod in example 1, step 1h.

Step 67c: Preparation of 6-(tert-butyl)-9-(2-(cylcopropylmethylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(2-(cylcopropylmethylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (2.7 mg) as yellow solid was prepared by using ethyl6-(tert-butyl)-9-(2-(cylcopropylmethylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(53 mg, 0.105 mmol) according to method in example 1, step 1i. ¹H NMR(400 MHz, DMSO-d₆): δ 8.77 (s, 1H), 8.52 (s, 2H), 7.64 (s, 1H), 7.61 (s,1H), 7.45-7.52 (m, 2H), 4.63-4.61 (m, 1H), 3.92 (s, 3H), 3.40-3.38 (m,2H), 3.20 (t, J=6.3 Hz, 2H), 1.09-1.06 (m, 1H), 0.74 (s, 9H), 0.45-0.39(m, 2H), 0.26-0.20 (m, 2H). MS observed (ESI⁺) [(M+H)⁺]: 475.

Example 686-(tert-butyl)-9-(2-chloropyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 68a: Preparation of ethyl6-(tert-butyl)-9-(2-chloropyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(2-chloropyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylateas brown solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.115 mmol) and (2-chloropyrimidin-5-yl)boronic acid (23.7 mg,0.15 mmol) according to method in example 1, step 1h.

Step 68b: Preparation of6-(tert-butyl)-9-(2-chloropyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

To a solution of ethyl6-(tert-butyl)-9-(2-chloropyrimidin-5-yl)-1-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylatein CH₃—CN (3 m) and water (1 mL) was added lithium hydroxide hydrate(19.3 mg, 0.46 mmol), and the mixture was stirred at RT for 1 h. Themixture was concentrated, and the resulted residue was dissolved inwater (20 mL), extracted with EtOAc (20 mL×5), and the water phase wasacidified with 1M HCl till pH=2, extracted with EtOAc (10 mL×5), and thecombined organic phase was washed with water (20 mL×5), and thenconcentrated to provide6-(tert-butyl)-9-(2-chloropyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (20.4 mmol) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 16.43 (s,1H), 8.97 (s, 2H), 8.76 (s, 1H), 7.67 (s, 2H), 7.58 (s, 1H), 4.61 (s,1H), 3.91 (s, 3H), 3.33-3.30 (m, 2H), 0.70 (s, 9H). MS observed (ESI⁺)[(M+H)⁺]: 440.

Example 699-(2-(azetidin-1-yl)pyrimidin-5-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 69a: Preparation of (2-(azetidin-1-yl)pyrimidin-5-yl)boronic Acid

To a solution of (2-chloropyrimidin-5-yl)boronic acid (100 mg, 0.63mmol) in DMF (3 mL) was added azetidine hydrochloride (235.7 mg, 2.52mmol), and the reaction mixture was heated at 80° C. and stirred for 16h. LC-MS showed that the reaction was completed, and the crude(2-(azetidin-1-yl) pyrimidin-5-yl)boronic acid was directly used fornext stage without further purification.

Step 69b: Preparation of ethyl9-(2-(azetidin-1-yl)pyrimidin-5-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl9-(2-(azetidin-1-yl)pyrimidin-5-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(92 mg) as brown solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(200 mg, 0.46 mmol) and (2-(azetidin-1-yl)pyrimidin-5-yl)boronic acid inDMF (3 mL, 0.21 M) from step 69a according to method in example 1, step1h.

Step 69c: Preparation of9-(2-(azetidin-1-yl)pyrimidin-5-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

9-(2-(azetidin-1-yl)pyrimidin-5-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (15.3 mg) as yellow solid was prepared by using ethyl9-(2-(azetidin-1-yl)pyrimidin-5-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(92 mg, 0.188 mmol) according to method in example 1, step 1i. ¹H NMR(400 MHz, DMSO-d₆): δ 16.57 (s, 1H), 8.78 (s, 1H), 8.56 (s, 2H), 7.65(s, 1H), 7.62 (s, 1H), 7.46 (s, 1H), 4.64-4.61 (m, 1H), 4.09 (t, J=7.5Hz, 4H), 3.91 (s, 3H), 3.45-3.35 (m, 2H), 2.37-2.30 (m, 2H), 0.74 (s,9H). MS observed (ESI⁺) [(M+H)⁺]: 475.

Example 70 Ethyl6-(tert-butyl)-9-(1-(1-ethoxy-2-methyl-1-oxoprop-2-yl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Step 70: Preparation of ethyl6-(tert-butyl)-9-(1-(1-ethoxy-2-methyl-1-oxoprop-2-yl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(1-(1-ethoxy-2-methyl-1-oxoprop-2-yl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(7 mg) as white solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(50 mg, 0.115 mmol) and ethyl2-methyl-2-(2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)propanoate(46 mg, 0.138 mmol) according to method in example 16, step 16a. ¹H NMR(400 MHz, DMSO-d₆): δ 8.37 (s, 1H), 7.90 (s, 1H), 7.70 (d, J=8.0 Hz,1H), 7.47 (s, 1H), 7.33 (s, 1H), 7.09 (s, 1H), 6.45 (d, J=8.0 Hz, 1H),4.36-4.34 (m, 1H), 4.25-4.20 (m, 2H), 4.13-3.99 (m, 4H), 3.90 (s, 3H),1.23 (s, 6H), 1.12-1.07 (m, 6H), 0.74 (s, 9H). MS observed (ESI⁺)[(M+H)⁺]: 563.

Example 71 Ethyl6-(tert-butyl)-9-(1-(2-ethoxy-2-oxoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Step 71: Preparation of ethyl6-(tert-butyl)-9-(1-(2-ethoxy-2-oxoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(1-(2-ethoxy-2-oxoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(12 mg) as light yellow solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and ethyl2-(2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)acetate(85 mg, 0.28 mmol) according to method in example 16, step 16a. ¹H NMR(400 MHz, DMSO-d₆): δ 8.41-8.37 (m, 1H), 7.99 (s, 1H), 7.75 (d, J=8.0Hz, 1H), 7.48 (s, 1H), 7.34 (s, 1H), 7.12-7.10 (m, 1H), 6.47 (d, J=8.0Hz, 1H), 4.76 (s, 2H), 4.36-4.13 (m, 4H), 3.90 (s, 3H), 3.75-3.70 (m,1H), 3.26-3.22 (m, 2H), 1.29-1.22 (m, 6H), 0.74 (s, 9H). MS observed(ESI⁺) [(M+H)⁺]: 535.

Example 72 Ethyl6-(tert-butyl)-9-(1-(3-ethoxy-3-oxopropyl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Step 72: Preparation of ethyl6-(tert-butyl)-9-(1-(3-ethoxy-3-oxopropyl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(1-(3-ethoxy-3-oxopropyl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(4.4 mg) as light yellow solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(80 mg, 0.18 mmol) and ethyl3-(2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)-propanoate(80 mg, 0.22 mmol) according to method in example 16, step 16a. ¹H NMR(400 MHz, DMSO-d₆): δ 8.40-8.37 (m, 1H), 7.97 (s, 1H), 7.70 (d, J=8.0Hz, 1H), 7.47 (s, 1H), 7.35 (s, 1H), 7.11-7.09 (m, 1H), 6.44 (d, J=8.0Hz, 1H), 4.36-4.15 (m, 4H), 4.09-4.04 (m, 2H), 3.90 (s, 3H), 3.75-3.70(m, 1H), 3.24-3.20 (m, 2H), 2.78 (t, J=8.0 Hz, 2H), 1.29-1.25 (m, 3H),1.16-1.13 (m, 3H), 0.74 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 549.

Example 736-(tert-butyl)-9-(2-(4-carboxypiperidin-1-yl)pyrimidin-5-yl)-1-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic Acid

Step 73a: Preparation of (2-(4-(methoxycarbonyl)piperidin-1-yl)pyrimidin-5-yl)boronic Acid

(2-(4-(methoxycarbonyl)piperidin-1-yl)pyrimidin-5-yl)boronic acid (150mg) was prepared by using (2-chloropyrimidin-5-yl)boronic acid (200 mg,1.26 mmol) and methyl piperidine-4-carboxylate hydrochloride (452 mg,2.52 mmol) according to method in example 67, step 67a.

Step 73b: Preparation of6-(tert-butyl)-10-methoxy-9-(2-(4-(methoxycarbonyl)piperidin-1-yl)pyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-10-methoxy-9-(2-(4-(methoxycarbonyl)piperidin-1-yl)pyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (20 mg) as colorless oil was prepared by using9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (150 mg, 0.37 mmol) and (2-(4-(methoxycarbonyl)piperidin-1-yl)pyrimidin-5-yl)boronic acid (148 mg, 0.56 mmol) accordingto method in example 1, step 1h.

Step 73c: Preparation of 6-(tert-butyl)-9-(2-(4-carboxypiperidin-1-yl)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(2-(4-carboxypiperidin-1-yl)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (3.0 mg) as yellow solid was prepared by using6-(tert-butyl)-10-methoxy-9-(2-(4-(methoxycarbonyl)piperidin-1-yl)pyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (20 mg, 0.037 mmol) according to method in example 1, step 1i. ¹HNMR (DMSO-d₆, 400 MHz): δ 16.55 (s, 1H), 12.23 (s, 1H), 8.77 (s, 1H),8.60 (s, 2H), 7.64 (s, 1H), 7.62 (s, 1H), 7.48 (s, 1H), 4.66-4.51 (m,4H), 3.92 (s, 3H), 3.45-3.37 (m, 2H), 3.12-3.09 (m, 2H), 1.92-1.89 (m,2H), 1.55-1.48 (m, 2H), 0.74 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 533.

Example 74 Ethyl6-(tert-butyl)-9-(1-(1-ethoxy-1-oxoprop-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Step 74: Preparation of ethyl6-(tert-butyl)-9-(1-(1-ethoxy-1-oxoprop-2-yl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(1-(1-ethoxy-1-oxoprop-2-yl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(18.4 mg) as light yellow solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(80 mg, 0.18 mmol) and ethyl2-(2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)propanoate(89 mg, 0.28 mmol) according to method in example 16, step 16a. ¹H NMR(400 MHz, DMSO-d₆): δ 8.41-8.37 (m, 1H), 7.97 (s, 1H), 7.72 (d, J=8.0Hz, 1H), 7.48 (s, 1H), 7.39-7.38 (m, 1H), 7.12-7.10 (m, 1H), 6.46 (d,J=8.0 Hz, 1H), 5.20-5.17 (m, 1H), 4.36-4.20 (m, 2H), 4.15-4.10 (m, 2H),3.91 (s, 3H), 3.75-3.64 (m, 1H), 3.31-3.23 (m, 2H), 1.59 (d, J=8.0 Hz,3H), 1.29-1.23 (m, 3H), 1.19-1.15 (m, 3H), 0.74 (s, 9H). MS observed(ESI⁺) [(M+H)⁺]: 549.

Example 75 Ethyl6-(tert-butyl)-9-(1-(4-ethoxy-4-oxobutyl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Step 75: Preparation of ethyl6-(tert-butyl)-9-(1-(4-ethoxy-4-oxobutyl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(1-(4-ethoxy-4-oxobutyl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(33 mg) as light yellow solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(80 mg, 0.18 mmol) and ethyl4-(2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)butanoate (93 mg, 0.28 mmol) according to method in example 16,step 16a. ¹H NMR (400 MHz, DMSO-d₆): δ 8.41-8.37 (m, 1H), 7.92-7.91 (m,1H), 7.69-7.66 (m, 1H), 7.47 (s, 1H), 7.37 (m, 1H), 7.11-7.09 (m, 1H),6.43 (d, J=8.0 Hz, 1H), 4.36-4.20 (m, 2H), 4.06-4.01 (m, 2H), 3.99-3.95(m, 2H), 3.90 (s, 3H), 3.75 (s, 1H), 3.29-3.22 (m, 2H), 2.35 (t, J=8.0Hz, 2H), 1.98-1.91 (m, 2H), 1.29-1.23 (m, 3H), 1.18-1.14 (m, 3H), 0.74(s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 563.

Example 766-(tert-butyl)-9-(2-(cyclobutylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 76a: Preparation of (2-(cyclobutylamino)pyrimidin-5-yl)boronic Acid

(2-(cyclobutylamino)pyrimidin-5-yl)boronic acid (54 mg) as yellow oilwas prepared by using (2-chloropyrimidin-5-yl)boronic acid (100 mg, 0.63mmol) and cyclobutylamine (179 mg, 2.52 mmol) according to method inexample 67, step 67a.

Step 76b: Preparation of ethyl 6-(tert-butyl)-9-(2-(cyclobutylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(2-(cyclobutylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(74 mg) as brown solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido-[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and (2-(cyclo-butylamino)pyrimidin-5-yl)boronic acid(54 mg, 0.28 mmol) according to method in example 1, step 1h.

Step 76c: Preparation of6-(tert-butyl)-9-(2-(cyclobutylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(2-(cyclobutylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (35.5 mg) as yellow solid was prepared by using ethyl6-(tert-butyl)-9-(2-(cyclobutylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(74 mg, 0.147 mmol) according to method in example 1, step 1i. ¹H NMR(DMSO-d₆, 400 MHz): δ 16.56 (s, 1H), 8.77 (s, 1H), 8.51 (s, 1H), 7.70(d, J=7.5 Hz, 1H), 7.64 (s, 1H), 7.61 (s, 1H), 7.46 (s, 1H), 4.63-4.60(m, 1H), 4.46-4.33 (m, 1H), 3.92 (s, 3H), 3.44-3.35 (m, 2H), 2.31-2.18(m, 2H), 2.05-1.91 (m, 2H), 1.71-1.59 (m, 2H), 0.74 (s, 9H). MS observed(ESI⁺) [(M+H)⁺]: 475.

Example 776-(tert-butyl)-9-(2-(3-carboxypyrrolidin-1-yl)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic Acid

Step 77a: Preparation of (2-(3-(ethoxycarbonyl)pyrrolidin-1-yl)pyrimidin-5-yl)boronic Acid

2-(3-(ethoxycarbonyl)pyrrolidin-1-yl)pyrimidin-5-yl)boronic acid (104mg) as yellow oil was prepared by using (2-chloropyrimidin-5-yl)boronicacid (200 mg, 1.26 mmol) and ethyl pyrrolidine-3-carboxylatehydrochloride (452 mg, 2.52 mmol) according to method in example 67,step 67a.

Step 77b: Preparation of ethyl 6-(tert-butyl)-9-(2-(3-(ethoxycarbonyl)pyrrolidin-1-yl)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl6-(tert-butyl)-9-(2-(3-(ethoxycarbonyl)pyrrolidin-1-yl)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(55 mg) as brown solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(100 mg, 0.23 mmol) and (2-(3-(ethoxycarbonyl)piperidin-1-yl)pyrimidin-5-yl)boronic acid (74 mg, 0.28 mmol) accordingto method in example 1, step 1h.

Step 77c: Preparation of 6-(tert-butyl)-9-(2-(3-carboxypyrrolidin-1-yl)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(2-(3-carboxypyrrolidin-1-yl)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (10.6 mg) as yellow solid was prepared by using ethyl6-(tert-butyl)-9-(2-(3-ethoxycarbonylpyrrolidin-1-yl)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(55 mg, 0.096 mmol) according to method in example 1, step 1i. ¹H NMR(DMSO-d₆, 400 MHz): δ 8.77 (s, 1H), 8.59 (s, 2H), 7.63 (s, 1H), 7.62 (s,1H), 7.47 (s, 1H), 4.63-4.60 (m, 1H), 3.92 (s, 3H), 3.72 (d, J=7.0 Hz,2H), 3.63-3.51 (m, 3H), 3.44-3.40 (m, 2H), 2.22-2.13 (m, 2H), 0.75 (s,9H). MS observed (ESI⁺) [(M+H)⁺]: 519.

Example 786-(tert-butyl)-9-(2-((carboxymethyl)amino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

Step 78a: Preparation of(2-(methoxycarbonylmethylamino)pyrimidin-5-yl)boronic Acid

(2-(methoxycarbonylmethyl)aminopyrimidin-5-yl)boronic acid (35.9 mg) asyellow oil was prepared by using (2-chloropyrimidin-5-yl)boronic acid(100 mg, 0.63 mmol) and methyl glycinate hydrochloride (316 mg, 2.52mmol) according to method in example 67, step 67a.

Step 78b: Preparation of ethyl6-(tert-butyl)-10-methoxy-9-(2-((2-methoxy-2-oxoethyl)amino)pyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate

Ethyl 6-(tert-butyl)-10-methoxy-9-(2-((2-methoxy-2-oxoethyl)amino)pyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(25 mg) as brown solid was prepared by using ethyl9-bromo-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(60 mg, 0.14 mmol) and (2-(methoxycarbonylmethyl)aminopyrimidin-5-yl)boronic acid (35.9 mg, 0.17 mmol) according tomethod in example 1, step 1h.

Step 78c: Preparation of 6-(tert-butyl)-9-(2-((carboxymethyl)amino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicAcid

6-(tert-butyl)-9-(2-((carboxymethyl)amino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid (1.2 mg) as yellow solid was prepared by using ethyl6-(tert-butyl)-10-methoxy-9-(2-((2-methoxy-2-oxoethyl)amino)pyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate(25 mg, 0.48 mmol) according to method in example 1, step 1i. ¹H NMR(DMSO-d₆, 400 MHz): δ 8.77 (s, 1H), 8.53 (s, 2H), 7.64 (s, 1H), 7.61 (s,1H), 7.47 (s, 1H), 4.64-4.60 (m, 1H), 3.92 (s, 3H), 3.85 (d, J=5.4 Hz,2H), 3.62-3.57 (m, 2H), 0.74 (s, 9H). MS observed (ESI⁺) [(M+H)⁺]: 479.

The biological implementation data are described in detail below tofurther elaborate the technical scheme of the invention.

Materials and Methods

HBV Cell Line:

HepG2.2.15 cells (Sells et al, Proc Natl Acad Sci USA. 1987 February;84(4):1005-9.), a constitutively HBV-expressing cell line, were culturedin DMEM medium supplemented with 10% FBS and 400 g/mL G418, andmaintained in 5% CO₂ at 37° C.

HBsAg Assay:

HepG2.2.15 cells were seeded into 96-well plates at 3×10⁴ cells/well.The next day, the cells were treated with a five-fold serial dilutionseries of the compound in DMSO. The final DMSO concentration in allwells was 0.5% and 0.5% DMSO was used as no drug control. After fourdays of incubation with compounds, the supernatants were harvested andmeasured for HBsAg concentration

The HBsAg chemiluminescence immunoassay (CLIA) kit was used to measurethe levels of secreted HBsAg. Specifically, 50 μL of culture supernatantwas transferred to the CLIA assay plate and 50 μL of enzyme conjugatereagent was added into each well. The plates were sealed and incubatedfor 1 hour at room temperature. The supernatant-enzyme-mixture wasdiscarded and wells were washed for 6 times. The residual liquid wasremoved by plating on tissue paper. 25 μL of substrate A and B wereadded into each well. Luminance was measured using a spectrometer (TecanInfinite® F200) after 10 minutes incubation. IC₅₀ value was extrapolatedbased the dose-response curves generated from the data.

Results

The compounds of example 1 to example 78 were tested for their capacityto inhibit HBsAg as described herein and the results are given in Table3.

TABLE 3 Activity Data in HBsAg assay Example No. IC₅₀ (uM) Examples No.IC₅₀ (uM) 1 0.014 2 0.008 3 0.018 4 0.024 5 0.014 6 0.006 7 0.036 80.009 9 0.290 10 0.006 11 0.003 12 0.002 13 0.018 14 0.002 15 0.004 160.002 17 0.025 18 0.077 19 0.068 20 0.007 21 0.016 22 0.007 23 0.040 240.008 25 0.007 26 0.008 27 0.004 28 0.0002 29 0.012 30 0.013 31 0.826 320.097 33 0.020 34 0.036 35 0.290 36 0.010 37 0.009 38 0.005 39 0.025 400.006 41 0.002 42 0.002 43 0.001 44 0.010 45 0.014 46 0.003 47 0.002 480.068 49 0.014 50 0.0005 51 0.0008 52 0.012 53 1.396 54 0.001 55 0.000856 0.001 57 0.001 58 0.004 59 0.010 60 0.0001 61 0.004 62 0.005 63 0.02764 0.007 65 0.080 66 0.0008 67 0.0003 68 0.0006 69 0.005 70 0.044 710.192 72 0.565 73 0.067 74 0.129 75 0.466 76 0.0004 77 0.150 78 0.045

The cytotoxicity CC₅₀ of part of the examples was measured according tomethods below:

HepG2.2.15 cells were seeded into 96-well white plate at 5000 cells/welland treated with serially diluted compounds. The plates were incubatedin incubator with 5% CO₂ at 37° C. for four days. The plate was takenout of incubator and adapted to room temperature for 30 minutes,followed by adding 25 μl CellTiter-Glo (Promega) reagent into each welland vortexed at room temperature before being measured for luminanceusing spectrometer (Tecan Infinite® F200). The CC₅₀ of each compound wasdefined as the compound concentration at which the treated well's cellviability is 50% compared to that of the DMSO treated well. The assayresults were given in table 4.

TABLE 4 CC₅₀ of part of the examples Example No. CC₅₀ Example No. CC₅₀18 B 19 B 20 A 21 B 22 B 24 B 25 B 28 A 31 B 32 B 37 B 50 B 51 A 60 B 63B 69 B 70 B 71 A 72 B 73 A 74 B 75 B (A: CC₅₀ > 100 μM; B: 100 μM >CC₅₀ > 50 μM)

The assay results indicated that none of the examples showed apparentcytotoxicity (CC₅₀>50 μM). Currently all the anti-HBV drugs on marketare nucleotide/nucleoside analogs and work as HBV polymerase inhibitors.However, these inhibitors can also interfere with human DNA and RNApolymerases and lead to undesired toxicities, while the compounds ofthis invention are non-nucleoside analogs and do not elicitaforementioned side-effects.

A single intravenous injection (IV, dose 2 mg/kg) and a single oraladministration (PO, dose 10 mg/kg) in ICR mice were used to assess thepharmacokinetic properties of several examples in this invention,respectively. The mean values of drug concentrations in plasma and liverare shown in Table 5 below.

TABLE 5 Mean value and ratio of drug concentrations in plasma and liverin ICR mice Mean drug concentrations IV (ng/mL) PO (ng/mL) Time (h)Plasma Liver L/P ratio Plasma Liver L/P ratio 1 247.3 11173.3 45.2 668.09093.3 13.6 8 2.4 30.2 12.8 18.7 292.5 15.7 24 1.2 4.1 3.5 1.7 6.4 3.7

As is shown in Table 5, the average drug concentration of severalexamples in this invention was significantly higher in liver than thatin plasma after intravenous administration and oral administration,indicating that the compound of this invention can be more enriched inthe liver, which can be used to liver disease therapy.

Further, it will be understood by those skilled in this field that allof the compounds involved in the above-described compounds of Formula I,the different realizations of compounds of Formula I, and theembodiments of the compounds of Formula I can be prepared tocorresponding isomers, solvates, hydrates, prodrugs, stable isotopederivatives, and pharmaceutically acceptable salts. Preferably, thecompound is made into a pharmaceutically acceptable derivative, which isany one of a prodrug, a salt, an ester, an amide, a salt of an ester, asalt of an amide, and a metabolite.

Further, the pharmaceutically acceptable salt refers to a conventionalnon-toxic salt obtained formed by using a inorganic acid (for example,hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid,sulfuric acid or phosphoric acid and the like) or an organic acid (forexample, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaricacid, benzenesulfonic acid, methanesulfonic acid, salicylic acid,succinic acid, citric acid, lactic acid, propionic acid, benzoic acid,p-toluenesulfonic acid, malic acid and the like) The reviews of suitablepharmaceutically acceptable salts can refer to: Berge S M et al, J.Pharm. Sci. 1977, 66, 1-19; Gould P L Int. J. Pharm 1986, 33, 201-277and Bighley et al., Encyclopedia of Pharmaceutical Technology, MarcelDekker Inc, New York, 1996, Vol. 13, pp. 453-497.

Further, an isotope can be introduced into any of the compounds of thisinvention by a stable isotope derivative, and the introduced isotope isany one of ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl.Specific isotope derivatives can be prepared by conventional techniques.

Further, as an actual product, the compound described herein can beformulated to any one of a tablet, a capsule, an injection, a granule, apulvis, a suppository, a pill, a cream, a paste, a gel, a powder, anoral solution, an inhalation, a suspension, a dry suspension, a patch,and a lotion.

Further, just as mentioned above, a mixture can also be formed with anyone of a pharmaceutically acceptable carrier, adjuvant and excipient.

Further, just as mentioned above, a composition comprising: thecompounds described herein and any one of the following substances: anHBV polymerase inhibitor, interferon α-2a, interferon α-2b, a pegylatedinterferon α-2a, ribavirin, an HBV preventive vaccine, an HBVtherapeutic vaccine, an HBV capsid inhibitor, an RNA replicationinhibitor of HBV, an siRNA, an inhibitor of HBsAg generation orsecretion, an HBV antibody, and a TLR7 agonist.

All of the compounds and mixtures, compositions and the like describedherein can be administered to a living body by any administration route.The administration route can be oral administration, intravenousinjection, intramuscular injection, subcutaneous injection, rectaladministration, vaginal administration, sublingual administration, nasalinhalation, oral inhalation, eye drop, or local or systemic transdermaladministration.

All the compounds and mixtures, compositions and the like describedherein can be formulated into a single dose containing the activecompound of this invention together with a carrier, an excipient and thelike. And the dosage form can be a tablet or a capsule, injections,granules, powders, suppositories, pills, creams, pastes, gels, powders,oral solutions, inhalants, suspensions, dry suspensions, patches,lotions and the like These dosage forms may contain ingredients commonlyused in pharmaceutical formulations, such as diluents, absorbents,wetting agents, binders, disintegrating agents, coloring agents, pHadjusting agents, antioxidants, bacteriostatic agents, isotonicityadjusting agents, anti-adhesive agent.

Suitable formulations of dosage forms described herein are availablefrom public sources, for example, Remington: The Science and Practice ofPharmacy, 21st edition, published by Lippincott Williams & Wilkins in2006 and Rowe, Raymond C. Handbook of Pharmaceutical Excipients,Chicago, Pharmaceutical Press Published in 2005. It can therefore beeasily prepared by those skilled in this field.

The dosage of the compounds of this invention can be 0.01 to 500 mg/kgper day depending on the individual nature, intensity, age, sex, bodyweight, route of administration, etc. Preferably, the daily dose is1-100 mg/kg, which can be administered in a single or multiple doses.

It is understood by those skilled in this field that all of thecompounds involved in this invention and mixtures, compositions and thelike comprising the compounds of the present invention are typicallyused for medical use, in particular for the prevention or treatment ofhepatitis B virus infection. The specific indications are as follows:The novel compound described herein can inhibit the production orsecretion of hepatitis B surface antigen (HBsAg), thus it can be used totreat and prevent HBV infection.

The novel compound described herein can be used to inhibit theproduction or secretion of hepatitis B surface antigen (HBsAg) The novelcompound described herein can be used to treat and prevent HBV infectionFurther, the compounds of the formula I in this invention can be used incombination with other drugs, including HBV polymerase inhibitors, suchas lamivudine, telbivudine, tenofovir disoproxil fumarate, AdelphiDivonide, entecavir or tenofovir alafenamide fumaric acid; interferonalpha-2a; interferon alpha-2b; peginterferon alfa-2a; ribavirin; HBVprophylactic vaccine; HBV treatment vaccine; HBV capsid inhibitor; HBVRNA replication inhibitor, siRNA; HBsAg production or secretioninhibitor; HBV antibody; TLR 7 agonist.

The specific embodiments of this invention have been described above. Itshould be understood that the present invention is not limited to thespecific embodiments described above, and various modifications andchanges can be made by those skilled in this field, this does not affectthe substance of the present invention.

The invention claimed is:
 1. A compound of general formula I:

wherein: R is any one of hydrogen and C₁₋₆ alkyl; R¹ is any one ofhydrogen, deuterium, halogen, C₁₋₆ alkyl, C₁₋₆ alkylamino, and C₁₋₆alkoxy; R² is any one of hydrogen, deuterium, halogen, C₁₋₆ alkyl, C₁₋₆alkyl substituted with at least one fluorine, C₃₋₇ cycloalkyl, C₁₋₆alkylamino, C₁₋₆ alkoxy, and heterocycloalkyl; Ar is any one of phenyl,thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,pyridin-2(1H)-keto, pyridin-4(1H)-keto, pyrrolyl, pyrazolyl, thiazolyl,1, 2, 3-triazolyl, 1, 2, 4-triazolyl, imidazolyl, tetrazolyl,isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, naphthyl,benzothiophenyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuryl,quinolyl, isoquinolyl, and quinazolinyl; R³ is any one of hydrogen,deuterium, halogen, cyano, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkylamino,C₁₋₆ alkoxy, and heterocycloalkyl; R⁴ is any one of hydrogen, deuterium,and C₁₋₆ alkyl; R⁵ is any one of hydrogen, deuterium, C₁₋₆ alkyl, C₁₋₆alkyl substituted with at least one fluorine, and C₃₋₇ cycloalkyl, anenantiomer, a diastereomer, a solvate, a hydrate, a prodrug, a stableisotope derivative or a pharmaceutically acceptable salt thereof.
 2. Thecompound according to claim 1, wherein Ar is substituted with any one ormore of deuterium, halogen, hydroxy, amino, cyano, C₁₋₆ alkyl, asubstituted C₁₋₆ alkyl, C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxyC₁₋₆ alkoxy, C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₃₋₇ cycloalkylamino,C₃₋₇ heterocycloalkylamino, C₃₋₇ cycloalkyl C₁₋₆ alkylamino, carboxylC₁₋₆ alkylamino, —C₃₋₇ heterocycloalkyl-R⁶, —C(═O)—R⁶, —C₁₋₆alkyl-C(═O)—R⁶, —S(═O)₂—R⁶, —C₁₋₆ alkyl-S(═O)₂—R⁶, —N(R⁷)—C(═O)—R⁸,—C₁₋₆ alkylamino-C(═O)—C₁₋₆ alkyl, and —C₁₋₆ alkylamino-C(═O)-amino C₁₋₆alkyl, wherein the substituted C₁₋₆ alkyl is substituted with any one ormore of fluorine, hydroxy, cyano, aryl, heteroaryl, amino, C₁₋₆ alkoxy,C₁₋₆ alkylamino, C₃₋₇ cycloalkyl, carboxyl, and C₃₋₇ heterocycloalkyl;wherein, R⁶ is any one of hydroxy, amino, carboxyl, C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇cycloalkylamino, C₃₋₇ heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl; R⁷is any one of hydrogen, deuterium, C₁₋₆ alkyl, and C₃₋₇ cycloalkyl; R⁸is any one of hydrogen, deuterium, C₁₋₆ alkyl, aryl, heteroaryl, C₃₋₇cycloalkyl, aryl C₁₋₆ alkyl, heteroaryl C₁₋₆ alkyl, and C₃₋₇heterocycloalkyl.
 3. The compound according to claim 1, wherein R is anyone of hydrogen, methyl, ethyl, propyl, isopropyl, and tert-butyl; R¹ isany one of hydrogen, deuterium, fluorine, chlorine, bromine, methyl,ethyl, isopropyl, tert-butyl, methylamino, ethylamino, methoxy, ethoxy,and isopropoxy; R² is any one of hydrogen, deuterium, fluorine,chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl,trifluoromethyl, trifluoromethylmethyl, cyclopropyl, cyclopentyl,methylamino, ethylamino, methoxy, ethoxy, isopropoxy, pyrrolidinyl, andmorpholinyl; Ar is phenyl substituted with any one or more of deuterium,fluorine, chlorine, bromine, hydroxy, cyano, methyl, ethyl,trifluoromethyl, trifluoromethylmethyl, hydroxymethyl, cyanomethyl,benzyl, pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,morpholinylethyl, methoxy, and methylamino; or pyrazolyl substitutedwith any one or more of deuterium, fluorine, chlorine, bromine, hydroxy,cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, benzyl,pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, carboxypropyl, morpholinylethyl, methoxy, methylamino,oxetanyl, piperidyl, and ethoxycarbonylethyl; or pyridinyl substitutedwith any one or more of deuterium, fluorine, chlorine, bromine, hydroxy,amino, cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl,methoxymethyl, methoxyethyl, methoxypropyl, methylaminoethyl,morpholinylethyl, morpholinyl, piperidyl, piperazinyl, pyrrolidinyl,azetidinyl, methoxy, methoxyethoxy, methylamino, dimethylamino,cyclopropylamino, cyclobutylamino, cyclopropylmethylamino,4-hydroxypiperidyl, 4-methylpiperazinyl, 4-ethylpiperazinyl,4-acetylpiperazinyl, ethoxycarbonylethyl, acetylamino, andcarboxymethylamino; or 1, 2, 4-triazolyl substituted with any one ormore of deuterium, fluorine, chlorine, bromine, hydroxy, amino, methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,difluoromethyl, trifluoromethyl, trifluoromethylmethyl, hydroxymethyl,hydroxyethyl, hydroxypropyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, and morpholinylethyl; or thiazolyl substituted with anyone or more of deuterium, fluorine, chlorine, bromine, hydroxy, amino,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, aminomethyl,methoxymethyl, methoxyethyl, methoxypropyl, methylaminoethyl,cyclopropylmethyl, carboxymethyl, carboxyethyl, carboxypropyl,morpholinylethyl, oxetanyl, piperidyl, morpholinyl, piperazinyl,4-hydroxypiperidyl, 4-methylpiperazinyl, and ethoxycarbonylethyl; orpyrimidyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, amino, cyano, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxyethyl, cyanomethyl,aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, azetidinyl,piperidyl, piperazinyl, methoxy, methylamino, dimethylamino,cyclopropylamino, cyclopropylmethylamino, 4-ethylpiperazinyl,ethoxycarbonylethyl, 4-carboxypiperidyl, cyclobutylamino,3-carboxypyrrolidinyl, and carboxymethylamino; or pyridin-2(1H)-ketosubstituted with any one or more of deuterium, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxyethyl, cyanomethyl,aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, piperidyl,piperazinyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, andethoxycarbonylpropyl; R³ is any one of hydrogen, deuterium, fluorine,chlorine, bromine, methyl, ethyl, and cyano; R⁴ is any one of hydrogen,deuterium, methyl, and ethyl; R⁵ is any one of hydrogen, deuterium,methyl, ethyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,trifluoromethyl, trifluoromethylmethyl, and cyclopropyl.
 4. The compoundaccording to claim 1, wherein R is any one of hydrogen and C₁₋₆ alkyl;R¹ is any one of hydrogen, deuterium, halogen, and C₁₋₆ alkyl; R² is anyone of hydrogen, deuterium, halogen, C₁₋₆ alkyl, C₁₋₆ alkyl substitutedwith at least one fluorine, C₃₋₇ cycloalkyl, and C₁₋₆ alkoxy; Ar is anyone of phenyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,pyridin-2(1H)keto, pyridin-4(1H)-keto, pyrrolyl, pyrazolyl, thiazolyl,1, 2, 3-triazolyl, 1, 2, 4-triazolyl, imidazolyl, tetrazolyl,isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, and oxadiazolyl; R³ isany one of hydrogen, deuterium, halogen, cyano, C₁₋₆ alkyl, and C₃₋₇cycloalkyl; R⁴ is any one of hydrogen, deuterium, and C₁₋₆ alkyl; R⁵ isany one of hydrogen, deuterium, C₁₋₆ alkyl, C₁₋₆ alkyl substituted withat least one fluorine, and C₃₋₇ cycloalkyl.
 5. The compound according toclaim 4, wherein Ar is substituted with any one or more of deuterium,halogen, hydroxy, cyano, amino, C₁₋₆ alkyl, a substituted C₁₋₆ alkyl,C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy C₁₋₆ alkoxy, C₁₋₆alkylamino, di-C₁₋₆ alkylamino, C₃₋₇ cycloalkylamino, C₃₋₇heterocycloalkylamino, C₃₋₇ cycloalkyl C₁₋₆ alkylamino, carboxyl C₁₋₆alkylamino, —C₃₋₇ heterocycloalkyl-R⁶, —C(═O)—R⁶, —C₁₋₆ alkyl-C(═O)—R⁶,—S(═O)₂—R⁶, —C₁₋₆ alkyl-S(═O)₂—R⁶, and —N(R⁷)—C(═O)—R⁸, wherein thesubstituted C₁₋₆ alkyl is substituted with any one or more of fluorine,hydroxy, cyano, amino, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkyl,carboxyl, and C₃₋₇ heterocycloalkyl; wherein R⁶ is any one of hydroxy,amino, carboxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl,C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkylamino, C₃₋₇heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl; R⁷ is any one of hydrogen,deuterium, and C₁₋₆ alkyl; R⁸ is any one of hydrogen, deuterium, C₁₋₆alkyl, C₃₋₇ cycloalkyl, and C₃₋₇ heterocycloalkyl.
 6. The compoundaccording to claim 4, wherein R is any one of hydrogen, methyl, ethyl,and isopropyl; R¹ is any one of hydrogen, deuterium, fluorine, chlorine,bromine, methyl, ethyl, isopropyl, and tert-butyl; R² is any one ofhydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl,isopropyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl,cyclopropyl, cyclopentyl, methoxy, ethoxy, and isopropoxy; Ar is phenylsubstituted with any one or more of deuterium, fluorine, chlorine,bromine, hydroxy, cyano, methyl, ethyl, trifluoromethyl,trifluoromethylmethyl, hydroxymethyl, cyanomethyl, benzyl,pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,morpholinylethyl, methoxy, and methylamino; or pyrazolyl substitutedwith any one or more of deuterium, fluorine, chlorine, bromine, hydroxy,cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, benzyl,pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, carboxypropyl, morpholinylethyl, methoxy, methylamino,oxetanyl, piperidyl, and ethoxycarbonylethyl; or pyridinyl substitutedwith any one or more of deuterium, fluorine, chlorine, bromine, hydroxy,amino, cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl,methoxymethyl, methoxyethyl, methoxypropyl, methylaminoethyl,morpholinylethyl, morpholinyl, piperidyl, piperazinyl, pyrrolidinyl,azetidinyl, methoxy, methoxyethoxy, methylamino, dimethylamino,cyclopropylamino, cyclobutylamino, cyclopropylmethylamino,4-hydroxypiperidyl, 4-methylpiperazinyl, 4-ethylpiperazinyl,4-acetylpiperazinyl, ethoxycarbonylethyl, acetylamino, andcarboxymethylamino; or 1, 2, 4-triazolyl substituted with any one ormore of deuterium, fluorine, chlorine, bromine, hydroxy, amino, methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,difluoromethyl, trifluoromethyl, trifluoromethylmethyl, hydroxymethyl,hydroxyethyl, hydroxypropyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, and morpholinylethyl; or thiazolyl substituted with anyone or more of deuterium, fluorine, chlorine, bromine, hydroxy, amino,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, aminomethyl,methoxymethyl, methoxyethyl, methoxypropyl, methylaminoethyl,cyclopropylmethyl, carboxymethyl, carboxyethyl, carboxypropyl,morpholinylethyl, oxetanyl, piperidyl, morpholinyl, piperazinyl,4-hydroxypiperidyl, 4-methylpiperazinyl, and ethoxycarbonylethyl; orpyrimidyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, amino, cyano, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxyethyl, cyanomethyl,aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, azetidinyl,piperidyl, piperazinyl, methoxy, methylamino, dimethylamino,cyclopropylamino, cyclopropylmethylamino, 4-ethylpiperazinyl,ethoxycarbonylethyl, 4-carboxypiperidyl, cyclobutylamino,3-carboxypyrrolidinyl, and carboxymethylamino; or pyridin-2(1H)-ketosubstituted with any one or more of deuterium, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxyethyl, cyanomethyl,aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, piperidyl,piperazinyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, andethoxycarbonylpropyl; R³ is any one of hydrogen, deuterium, fluorine,chlorine, bromine, cyano, methyl, ethyl, and cyclopropyl; R⁴ is any oneof hydrogen, deuterium, methyl, and ethyl; R⁵ is any one of hydrogen,deuterium, methyl, ethyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, and cyclopropyl.
 7. The compound according to claim 1,wherein Ar is substituted with any one or more of deuterium, halogen,hydroxy, cyano, amino, C₁₋₆ alkyl, a substituted C₁₋₆ alkyl, C₃₋₇heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy C₁₋₆ alkoxy, C₁₋₆ alkylamino,alkylamino, C₃₋₇ cycloalkylamino, C₃₋₇ heterocycloalkylamino, C₃₋₇cycloalkyl C₁₋₆ alkylamino, carboxyl C₁₋₆ alkylamino, —C₃₋₇heterocycloalkyl-R⁶, —C(═O)—R⁶, —C₁₋₆ alkyl-C(═O)—R⁶, —S(═O)₂—R⁶, —C₁₋₆alkyl-S(═O)₂—R⁶, and —N(R⁷)—C(═O)—R⁸, wherein the substituted C₁₋₆ alkylis substituted with any one or more of fluorine, hydroxy, cyano, amino,C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkyl, carboxyl, and C₃₋₇heterocycloalkyl; wherein R⁶ is any one of hydroxy, amino, carboxyl,C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆alkylamino, C₃₋₇ cycloalkylamino, C₃₋₇ heterocycloalkylamino, and—C(═O)—C₁₋₆ alkyl; R⁷ is any one of hydrogen, deuterium, and C₁₋₆ alkyl;R⁸ is any one of hydrogen, deuterium, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, andC₃₋₇ heterocycloalkyl.
 8. The compound according to claim 7, wherein Ris any one of hydrogen, methyl, ethyl, and isopropyl; R¹ is any one ofhydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, andisopropoxy; R² is any one of hydrogen, deuterium, fluorine, chlorine,bromine, methylamino, ethylamino, methoxy, ethoxy, and isopropoxy; Ar isphenyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, cyano, methyl, ethyl, trifluoromethyl,trifluoromethylmethyl, hydroxymethyl, cyanomethyl, benzyl,pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,morpholinylethyl, methoxy, and methylamino; or pyrazolyl substitutedwith any one or more of deuterium, fluorine, chlorine, bromine, hydroxy,cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, benzyl,pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, carboxypropyl, morpholinylethyl, methoxy, methylamino,oxetanyl, piperidyl, and ethoxycarbonylethyl; or pyridinyl substitutedwith any one or more of deuterium, fluorine, chlorine, bromine, hydroxy,amino, cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl,methoxymethyl, methoxyethyl, methoxypropyl, methylaminoethyl,morpholinylethyl, morpholinyl, piperidyl, piperazinyl, pyrrolidinyl,azetidinyl, methoxy, methoxyethoxy, methylamino, dimethylamino,cyclopropylamino, cyclobutylamino, cyclopropylmethylamino,4-hydroxypiperidyl, 4-methylpiperazinyl, 4-ethylpiperazinyl,4-acetylpiperazinyl, ethoxycarbonylethyl, acetylamino, andcarboxymethylamino; or 1, 2, 4-triazolyl substituted with any one ormore of deuterium, fluorine, chlorine, bromine, hydroxy, amino, methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,difluoromethyl, trifluoromethyl, trifluoromethylmethyl, hydroxymethyl,hydroxyethyl, hydroxypropyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, and morpholinylethyl; or thiazolyl substituted with anyone or more of deuterium, fluorine, chlorine, bromine, hydroxy, amino,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, aminomethyl,methoxymethyl, methoxyethyl, methoxypropyl, methylaminoethyl,cyclopropylmethyl, carboxymethyl, carboxyethyl, carboxypropyl,morpholinylethyl, oxetanyl, piperidyl, morpholinyl, piperazinyl,4-hydroxypiperidyl, 4-methylpiperazinyl, and ethoxycarbonylethyl; orpyrimidyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, amino, cyano, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxyethyl, cyanomethyl,aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, azetidinyl,piperidyl, piperazinyl, methoxy, methylamino, dimethylamino,cyclopropylamino, cyclopropylmethylamino, 4-ethylpiperazinyl,ethoxycarbonylethyl, 4-carboxypiperidyl, cyclobutylamino,3-carboxypyrrolidinyl, and carboxymethylamino; or pyridin-2(1H)-ketosubstituted with any one or more of deuterium, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxyethyl, cyanomethyl,aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, piperidyl,piperazinyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, andethoxycarbonylpropyl; R³ is any one of hydrogen, deuterium, fluorine,chlorine, and bromine; R⁴ is hydrogen or deuterium; R⁵ is any one ofhydrogen, deuterium, methyl, ethyl, isopropyl, butyl, sec-butyl,isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl, andcyclopropyl.
 9. The compound according to claim 1, wherein Ar is phenylsubstituted with any one or more of deuterium, halogen, hydroxy, cyano,C₁₋₆ alkyl, a substituted C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆ alkylamino,wherein the substituted C₁₋₆ alkyl is substituted with any one or moreof fluorine, hydroxy, cyano, aryl, heteroaryl, amino, C₁₋₆ alkoxy, C₁₋₆alkylamino, C₃₋₇ cycloalkyl, carboxyl, and C₃₋₇ heterocycloalkyl. 10.The compound according to claim 1, wherein Ar is phenyl substituted withany one or more of deuterium, fluorine, chlorine, bromine, hydroxy,cyano, methyl, ethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, cyanomethyl, benzyl, pyrazolylmethyl, aminomethyl,methoxymethyl, methoxyethyl, methoxypropyl, methylaminoethyl,cyclopropylmethyl, carboxymethyl, morpholinylethyl, methoxy, andmethylamino.
 11. The compound according to claim 1, wherein Ar ispyrazolyl substituted with any one or more of deuterium, halogen,hydroxy, cyano, C₁₋₆ alkyl, a substituted C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkylamino, C₃₋₇ heterocycloalkyl, and —C₁₋₆ alkyl-C(═O)—R⁶, wherein thesubstituted C₁₋₆ alkyl is substituted with any one or more of fluorine,hydroxy, cyano, aryl, heteroaryl, amino, C₁₋₆ alkoxy, C₁₋₆ alkylamino,C₃₋₇ cycloalkyl, carboxyl, and C₃₋₇ heterocycloalkyl; wherein R⁶ is anyone of hydroxy, amino, carboxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkylamino,C₃₋₇ heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl.
 12. The compoundaccording to claim 1, wherein Ar is pyrazolyl substituted with any oneor more of deuterium, fluorine, chlorine, bromine, hydroxy, cyano,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, benzyl,pyrazolylmethyl, aminomethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, carboxypropyl, morpholinylethyl, methoxy, methylamino,oxetanyl, piperidyl, and ethoxycarbonylethyl.
 13. The compound accordingto claim 1, wherein Ar is pyridinyl substituted with any one or more ofdeuterium, halogen, hydroxy, amino, cyano, C₁₋₆ alkyl, a substitutedC₁₋₆ alkyl, and C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy C₁₋₆alkoxy, C₁₋₆ alkylamino, alkylamino, C₃₋₇ cycloalkylamino, C₃₋₇cycloalkyl C₁₋₆ alkylamino, carboxyl C₁₋₆ alkylamino, —C₃₋₇heterocycloalkyl-R⁶, —C₁₋₆ alkyl-C(═O)—R⁶, and —N(R⁷)—C(═O)—R⁸, whereinthe substituted C₁₋₆ alkyl is substituted with any one or more offluorine, C₁₋₆ alkoxy, C₁₋₆ alkylamino, and C₃₋₇ heterocycloalkyl;wherein R⁶ is any one of hydroxy, amino, carboxyl, C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇cycloalkylamino, C₃₋₇ heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl, R⁷is any one of hydrogen, deuterium, C₁₋₆ alkyl, and C₃₋₇ cycloalkyl; R⁸is any one of hydrogen, deuterium, C₁₋₆ alkyl, aryl, heteroaryl, C₃₋₇cycloalkyl, aryl C₁₋₆ alkyl, heteroaryl C₁₋₆ alkyl, and C₃₋₇heterocycloalkyl.
 14. The compound according to claim 1, wherein Ar ispyridinyl substituted with any one or more of deuterium, fluorine,chlorine, bromine, hydroxy, amino, cyano, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, trifluoromethyl,trifluoromethylmethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, morpholinylethyl, morpholinyl, piperidyl, piperazinyl,pyrrolidinyl, azetidinyl, methoxy, methoxyethoxy, methylamino,dimethylamino, cyclopropylamino, cyclobutylamino,cyclopropylmethylamino, 4-hydroxypiperidyl, 4-methylpiperazinyl,4-ethylpiperazinyl, 4-acetylpiperazinyl, ethoxycarbonylethyl,acetylamino, and carboxymethylamino.
 15. The compound according to claim1, wherein Ar is 1, 2, 4-triazolyl substituted with any one or more ofdeuterium, halogen, hydroxy, amino, C₁₋₆ alkyl, and C₁₋₆ alkylsubstituted with any one or more of fluorine, hydroxy, amino, C₁₋₆alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkyl, carboxyl, and C₃₋₇heterocycloalkyl.
 16. The compound according to claim 1, wherein Ar is1, 2, 4-triazolyl substituted with any one or more of deuterium,fluorine, chlorine, bromine, hydroxy, amino, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl,trifluoromethyl, trifluoromethylmethyl, hydroxymethyl, hydroxyethyl,hydroxypropyl, aminomethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl, andmorpholinylethyl.
 17. The compound according to claim 1, wherein Ar isthiazolyl substituted with any one or more of deuterium, halogen,hydroxy, amino, C₁₋₆ alkyl, a substituted C₁₋₆ alkyl, C₃₋₇heterocycloalkyl, —C₃₋₇ heterocycloalkyl-R⁶, and —C₁₋₆ alkyl-C(═O)—R⁶,wherein the substituted C₁₋₆ alkyl is substituted with any one or moreof fluorine, hydroxy, cyano, amino, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇cycloalkyl, carboxyl, and C₃₋₇ heterocycloalkyl; wherein R⁶ is any oneof hydroxy, amino, carboxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkylamino,C₃₋₇ heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl.
 18. The compoundaccording to claim 1, wherein Ar is thiazolyl substituted with any oneor more of deuterium, fluorine, chlorine, bromine, hydroxy, amino,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, aminomethyl,methoxymethyl, methoxyethyl, methoxypropyl, methylaminoethyl,cyclopropylmethyl, carboxymethyl, carboxyethyl, carboxypropyl,morpholinylethyl, oxetanyl, piperidyl, morpholinyl, piperazinyl,4-hydroxypiperidyl, 4-methylpiperazinyl, and ethoxycarbonylethyl. 19.The compound according to claim 1, wherein Ar is pyrimidyl substitutedwith any one or more of deuterium, halogen, hydroxy, amino, cyano, C₁₋₆alkyl, a substituted C₁₋₆ alkyl, C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy,C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₃₋₇ cycloalkylamino, C₃₋₇cycloalkyl C₁₋₆ alkylamino, carboxyl C₁₋₆ alkylamino, —C₃₋₇heterocycloalkyl-R⁶, and —C₁₋₆ alkyl-C(═O)—R⁶, wherein the substitutedC₁₋₆ alkyl is substituted with any one or more of fluorine, hydroxy,cyano, amino, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkyl, carboxyl,and C₃₋₇ heterocycloalkyl; wherein R⁶ is any one of hydroxy, amino,carboxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl, C₁₋₆alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkylamino, C₃₋₇heterocycloalkylamino, and —C(═O)—C₁₋₆ alkyl.
 20. The compound accordingto claim 1, wherein Ar is pyrimidyl substituted with any one or more ofdeuterium, fluorine, chlorine, bromine, hydroxy, amino, cyano, methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,difluoromethyl, trifluoromethyl, trifluoromethylmethyl, hydroxyethyl,cyanomethyl, aminoethyl, methoxymethyl, methoxyethyl, methoxypropyl,methylaminoethyl, cyclopropylmethyl, carboxymethyl, carboxyethyl,carboxypropyl, morpholinylethyl, morpholinyl, pyrrolidinyl, azetidinyl,piperidyl, piperazinyl, methoxy, methylamino, dimethylamino,cyclopropylamino, cyclopropylmethylamino, 4-ethylpiperazinyl,ethoxycarbonylethyl, 4-carboxypiperidyl, cyclobutylamino,3-carboxypyrrolidinyl, and carboxymethylamino.
 21. The compoundaccording to claim 1, wherein Ar is pyridin-2(1H)-keto substituted withany one or more of deuterium, C₁₋₆ alkyl, a substituted C₁₋₆ alkyl, C₃₋₇heterocycloalkyl, and —C₁₋₆ alkyl-C(═O)—R⁶, wherein the substituted C₁₋₆alkyl is substituted with any one or more of fluorine, hydroxy, cyano,amino, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₇ cycloalkyl, carboxyl, and C₃₋₇heterocycloalkyl; wherein R⁶ is any one of hydroxy, amino, carboxyl,C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆alkylamino, C₃₋₇ cycloalkylamino, C₃₋₇ heterocycloalkylamino, and—C(═O)—C₁₋₆ alkyl.
 22. The compound according to claim 1, wherein Ar ispyridin-2(1H)-keto substituted with any one or more of deuterium,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, difluoromethyl, trifluoromethyl, trifluoromethylmethyl,hydroxyethyl, cyanomethyl, aminoethyl, methoxymethyl, methoxyethyl,methoxypropyl, methylaminoethyl, cyclopropylmethyl, carboxymethyl,carboxyethyl, carboxypropyl, morpholinyl ethyl, morpholinyl,pyrrolidinyl, piperidyl, piperazinyl, ethoxycarbonylmethyl,ethoxycarbonylethyl, and ethoxycarbonylpropyl.
 23. The compoundaccording to claim 1, wherein R³ is hydrogen or deuterium.
 24. Thecompound according to claim 1, wherein R⁴ is hydrogen or deuterium. 25.The compound according to claim 1, wherein R⁵ is any one of hydrogen,deuterium, methyl, ethyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, trifluoromethyl, trifluoromethylmethyl, and cyclopropyl. 26.The compound according to claim 1, selected from the group consistingof:6-isopropyl-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-isopropyl-10-methoxy-2-oxo-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-isopropyl-10-methoxy-9-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;9-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;9-(1-isobutyl-1H-pyrazol-4-yl)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-isopropyl-10-methoxy-2-oxo-9-(1-propyl-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-isopropyl-10-methoxy-9-(6-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-2-oxo-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-9-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-9-(1-methyl-1H-pyrazol-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(1-(difluoromethyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(1,3-dimethyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-9-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-2-oxo-9-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid hydrochloride;6-(tert-butyl)-9-(1-isopropyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(1,4-dimethyl-1H-pyrazol-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(1-(carboxymethyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid; ethyl6-(tert-butyl)-9-(1-(3-ethoxy-3-oxopropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate;6-(tert-butyl)-9-(1-(2-carboxyethyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(1-(3-ethoxy-3-oxopropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(1-(3-carboxypropyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-9-(3-methyl-1H-pyrazol-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(1-(1-carboxyethyl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(1-(2-carboxypropan-2-yl)-1H-pyrazol-4-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-9-(2-methylthiazol-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-2-oxo-9-(1H-1,2,4-triazol-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(1-(carboxymethyl)-1H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(4-(3-hydroxypropyl)-4H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(1-(3-hydroxypropyl)-1H-1,2,4-triazol-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-2-oxo-9-phenyl-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(4-ethylphenyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-9-(4-methoxyphenyl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-9-(3-methoxyphenyl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-9-(6-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-9-(2-methylpyridin-4-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-9-(2-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-9-(6-morpholinopyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-2-oxo-9-(6-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-9-(6-(2-methoxyethoxy)pyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(6-(dimethylamino)pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-2-oxo-9-(6-(pyrrolidin-1-yl)pyridin-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-2-oxo-9-(6-(piperazin-1-yl)pyridin-3-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;9-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-9-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(6-fluoro-4-methylpyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(6-fluoropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;9-(6-(azetidin-1-yl)pyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(6-((cyclopropylmethyl)amino)pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;9-(6-(azetidin-1-yl)-4-methylpyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;9-(6-aminopyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid; ethyl6-(tert-butyl)-10-methoxy-9-(6-methylpyridin-3-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate;6-(tert-butyl)-9-(6-(cyclobutylamino)pyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;9-(6-acetamidopyridin-3-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-9-(2-methylpyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-2-oxo-9-(2-(pyrrolidin-1-yl)pyrimidin-5-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-9-(2-(methylamino)pyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(2-(dimethylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-9-(2-morpholinopyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(2-(cyclopropylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;9-(2-aminopyrimidin-5-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-10-methoxy-9-(2-methoxypyrimidin-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(2-((cyclopropylmethyl)amino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(2-chloropyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;9-(2-(azetidin-1-yl)pyrimidin-5-yl)-6-(tert-butyl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid; ethyl6-(tert-butyl)-9-(1-(1-ethoxy-2-methyl-1-oxopropan-2-yl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate;ethyl6-(tert-butyl)-9-(1-(2-ethoxy-2-oxoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate;ethyl6-(tert-butyl)-9-(1-(3-ethoxy-3-oxopropyl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate;6-(tert-butyl)-9-(2-(4-carboxypiperidin-1-yl)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid; ethyl6-(tert-butyl)-9-(1-(1-ethoxy-1-oxopropan-2-yl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate;ethyl6-(tert-butyl)-9-(1-(4-ethoxy-4-oxobutyl)-6-oxo-1,6-dihydropyridin-3-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate;6-(tert-butyl)-9-(2-(cyclobutylamino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid;6-(tert-butyl)-9-(2-(3-carboxypyrrolidin-1-yl)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid; and6-(tert-butyl)-9-(2-((carboxymethyl)amino)pyrimidin-5-yl)-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylicacid.